Dual modulators of 5ht2a and d3 receptors

ABSTRACT

The present invention relates to compounds of the formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , X and n are as defined in the specification as dual modulators of the serotonin 5-HT 2a  and dopamine D 3  receptors, their manufacture, pharmaceutical compositions containing them and their use for the treatment of psychotic disorders, as well as other diseases such as depression and anxiety, drug dependence, dementias and memory impairment.

PRIORITY TO RELATED APPLICATION(S)

This application is a continuation of U.S. application Ser. No.12/175,476, filed Jul. 18, 2008, now pending; which claims the benefitof European Patent Application No. 07113252.6, filed Jul. 26, 2007. Theentire contents of the above-identified applications are herebyincorporated by reference.

BACKGROUND OF THE INVENTION

Schizophrenia is characterized by complex symptomatology includingpositive symptoms, (i.e. delusions and hallucinations), and negativesymptoms, (i.e. anhedonia, restricted fluency and productivity ofthought and speech). In addition it is now well recognized thatcognitive impairment is the third major diagnostic category ofschizophrenia, characterized by loss in working memory as well as otherdeficits. Other symptoms include aggressiveness, depression and anxiety(Stahl, S. M. (2000) Essential Psychopharmacology. Neuroscientific Basisand Practical Applications. Cambridge University Press, second edition,Cambridge, UK). The different categories and the clinical features ofthe disorder are defined in diagnostic schemes such as DSM-IV(Diagnostic and statistical manual of mental disorders, 4^(th) edition)or ICD-10 (International classification of diseases, 10^(th) edition).

Currently used medications to treat schizophrenia, bipolar mania andother psychoses, include antipsychotics both typical (D₂/D₃ preferring)or the more recent atypicals, which exhibit polypharmacology interactingat multiple receptors (eg., D₁, D₂, D₃, D₄, 5-HT_(1A), 5-HT_(2A),5-HT_(2c), H₁, M₁, M₂, M₄, etc; Roth, B. L. et al. (2004) Magic shotgunsversus magic bullets: selectively non-selective drugs for mood disordersand schizophrenia. Nat. Rev. Drug Discov. 3, 353-359). Theseantipsychotics, although relatively successful (some patients exhibittreatment resistance) at treating the positive symptoms ofschizophrenia, are less effective at treating negative symptoms,cognitive deficits, and associated depression and anxiety, all of whichlead to reduced patient quality of life and socioeconomic problems(Lieberman, J. A. et al. Clinical Antipsychotic Trials of InterventionEffectiveness (CATIE) Investigators. (2005) Effectiveness ofantipsychotic drugs in patients with chronic schizophrenia. N. Engl. J.Med. 353, 1209-1223). Furthermore, patient compliance is compromised byprevalent side effects such as weight gain, extrapyramidal symptoms(EPS), and cardiovascular effects (Lieberman, J. A. et al. ClinicalAntipsychotic Trials of Intervention Effectiveness (CATIE)Investigators. (2005) Effectiveness of antipsychotic drugs in patientswith chronic schizophrenia. N. Engl. J. Med. 353, 1209-1223). In thecurrent invention, compounds with high affinity and greater selectivityfor D₃ and 5-HT_(2A) receptors are described and are proposed to treatpsychoses and other diseases, with fewer associated side affects.

Dopamine, a major catecholamine neurotransmitter, is involved in theregulation of a variety of functions which include emotion, cognition,motor functions, and positive reinforcement, (Purves, D. et al. (2004)Neuroscience. Sinauer, third edition, Sunderland, Mass.). The biologicalactivities of dopamine are mediated through G protein-coupled receptors(GPCRs) and in human, five different dopamine receptors D₁-D₅ have beenidentified, where the D₂-like receptors (D₂, D₃ and D₄) couple to theG-protein G_(αI) (Missale, C. et al. (1998) Dopamine receptors: fromstructure to function. Physiol. Rev. 78, 189-225). The D₃ dopaminereceptor is most highly expressed in the nucleus accumbens (Gurevich, E.V., Joyce, J. N. (1999) Distribution of dopamine D3 receptor expressingneurons in the human forebrain: comparison with D2 receptor expressingneurons. Neuropsychopharmacology 20, 60-80), and is proposed to modulatethe mesolimbic pathway consisting of neuronal projections from theventral tegmental area, hippocampus and amygdala to the nucleusaccumbens, which projects to the prefrontal and cingulate cortices aswell as various thalamic nuclei. The limbic circuit is thought to beimportant for emotional behavior and thus D₃ receptor antagonists areproposed to modulate psychotic symptoms such as hallucinations,delusions and thought disorder (Joyce, J. N. and Millan, M. J., (2005)Dopamine D3 receptor antagonists as therapeutic agents. Drug DiscoveryToday, 1 July, Vol. 10, No. 13, 917-25), while these antagonists sparethe D2 modulated striatal extrapyramidal system (associated with EPSinduction). In addition, it has been reported that drug naiveschizophrenic patients show altered levels of D₃ receptor expression(Gurevich, E. V. et al. (1997) Mesolimbic dopamine D3 receptors and useof antipsychotics in patients with schizophrenia. A postmortem study.Arch. Gen. Psychiatry 54, 225-232) and dopamine release (Laruelle, M.(2000) Imaging dopamine dysregulation in schizophrenia: implication fortreatment. Presented at Workshop Schizophr.: Pathol. Bases and Mech.Antipsychotic Action, Chicago), indicating that a disturbed homeostasisof dopamine plays an important role in the etiology of schizophrenicsymptoms.

The neurotransmitter serotonin is implicated in several psychiatricconditions including schizophrenia (Kandel, E. R. et al. (eds.; 2000)Principles of Neural Science, 3^(rd) edition Appleton & Lange, Norwalk,Conn.). The involvement of serotonin in psychotic disorders is suggestedby multiple studies, which include treatment in humans with thepsychotropic drug Lysergic acid (LSD; a serotonin agonist) that caninduce schizophrenia-like symptoms such as hallucinations (Leikin, J. B.et al. (1989) Clinical features and management of intoxication due tohallucinogenic drugs. Med. Toxicol. Adverse Drug Exp. 4, 324-350).Furthermore, altered brain distribution of serotonin receptors as wellas an altered serotonergic tone, have been detected in schizophrenicpatients (Harrison, P. J. (1999) Neurochemical alterations inschizophrenia affecting the putative receptor targets of atypicalantipsychotics. Focus on dopamine (D1, D3, D4) and 5-HT2A receptors. Br.J. Psychiatry Suppl. 38, 12-22).

In mammals serotonin exerts its biological activities through a familyof 14 5-HT GPCRs (Barnes, N. M., Sharp, T. (1999) A review of central5-HT receptors and their function. Neuropharmacology 38, 1083-1152). The5-HT_(2A) receptor is most prominently expressed in the prefrontalcortex and at lower levels in the basal ganglia and the hippocampus inhuman brain (Pompeiano, M. et al. (1994) Distribution of the serotonin5-HT2 receptor family mRNAs: comparison between 5-HT_(2A) and 5-HT2Creceptors. Brain Res. Mol. Brain. Res. 23, 163-178; Pazos, A., Probst,A., Palacios, J. M. (1987) Serotonin receptors in the human brain—IV.Autoradiographic mapping of serotonin-2 receptors. Neuroscience 21,123-139), and is coupled predominantly to the G-protein G_(αq) (Roth, B.L. et al. (1998) 5-Hydroxytryptamine-2-family receptors(5-hydroxytryptamine-2A, 5-hydroxytryptamine-2B,5-hydroxytryptamine-2C):where structure meets function. Pharmacol. Ther. 79, 231-257). Geneticlinkage studies of a 5-HT_(2A) polymorphism to schizophrenia (Spurlock,G. et al. (1998) A family based association study of T102C polymorphismin 5HT_(2A) and schizophrenia plus identification of new polymorphismsin the promoter. Mol. Psychiatry. 3, 42-49), as well as responsivenessto antipsychotic drugs (Arranz, M. J. et al. (2000) Pharmacogeneticprediction of clozapine response. Lancet 355, 1615-1616), furthersuggests a role for the 5-HT_(2A) receptor both in the treatment andpathology of psychosis. In addition, dopaminergic neurotransmissionappears to be under the afferent regulation of the 5-HT_(2A) receptor(Porras, G. et al. 5-HT2A and 5-HT2C/2B receptor subtypes modulatedopamine release induced in vivo by amphetamine and morphine in both therat nucleus accumbens and striatum. Neuropsychopharmacology 26,311-324-2002).

Overall 5-HT_(2A) receptor antagonists are proposed to be suitable forthe treatment of disorders associated with dysfunctional dopaminergicsystems. Moreover, 5-HT_(2A) receptor antagonism has been recognized asbeneficial for the treatment of psychosis (reviewed in de Angelis, L.(2002) 5-HT_(2A) antagonists in psychiatric disorders. Curr. Opin.Investig. Drugs 3, 106-112) and indeed is one of the defining featuresof so-called atypical antipsychotic drugs which are characterized by arelatively high affinity for the 5-HT_(2A)-relative to the D₂ receptor(Meltzer, H. Y. et al. (1989) Classification of typical and atypicalantipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKivalues. J. Pharmacol. Exp. Ther. 251, 238-246).

SUMMARY OF THE INVENTION

The present invention provides compounds of the general formula (I)

wherein:

-   each X is independently halogen, cyano; C₁₋₆-alkyl, C₁₋₆-alkoxy or    C₁₋₆-haloalkyl;-   n is 0, 1, 2 or 3;-   R¹ is H or C₁₋₆-alkyl;-   R² is

-   R³ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkoxy,    C₃₋₁₀-cycloalkyl, aryl, 4 to 10 membered heterocycloalkyl, or 5 to    10 membered heteroaryl, each of which is optionally substituted by    one to five substituents selected from the group consisting of:    -   halo,    -   cyano,    -   —SO₂—C₁₋₆-alkyl,    -   hydroxy,    -   C₁₋₆-alkyl,    -   C₁₋₆-haloalkyl,    -   —CO(O)—C₁₋₆-alkyl,    -   C₁₋₆-alkoxy optionally substituted by one or more R^(a),    -   C₃₋₁₀-cycloalkyl optionally substituted by one or more R^(a),    -   4 to 10 membered heterocycloalkyl optionally substituted by one        or more R^(a), aryl optionally substituted by one or more R^(a),    -   5 to 10 membered heteroaryl optionally substituted by one or        more R^(a), and —NR^(b)R^(c),        -   wherein R^(b) is H or C₁₋₆-alkyl and wherein R^(c) is H,            C₁₋₆-alkyl or aryl optionally substituted by one or more            R^(a);    -   wherein R^(a) is selected from:        -   halo,        -   cyano,        -   oxo,        -   hydroxy,        -   halobenzenesulfonyl,        -   C₁₋₆-alkyl        -   C₁₋₆-haloalkyl,        -   —NH(CO)—C₁₋₆-alkyl,        -   di(C₁₋₆)alkylamino,        -   —O(CO)—C₁₋₆-alkyl,        -   C₁₋₆-alkylsulfonyl,        -   C₁₋₆-alkoxy        -   C₁₋₆-haloalkoxy,        -   4 to 10 membered heterocycloalkyl        -   aryl,        -   aryloxy, and        -   5 to 10 membered heteroaryl;

as well as pharmaceutically acceptable salts thereof.

Compounds of formula (I) according to the invention are dual modulatorsof the serotonin 5-HT_(2a) and dopamine D₃ receptors.

The compounds of the invention have high affinity for the dopamine D₃and serotonin (5-Hydroxytryptamine; 5-HT) 5-HT_(2A) receptors and areeffective in the treatment of psychotic disorders, as well as otherdiseases such as depression and anxiety, drug dependence, dementias andmemory impairment. Psychotic disorders encompass a variety of diseases,which include schizophrenia, schizoaffective disorders, bipolar disease,mania, psychotic depression, and other psychoses involving paranoia anddelusions.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of the general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination. It must be noted that, as used in thespecification and the appended claims, the singular forms “a”, “an,” and“the” include plural forms unless the context clearly dictatesotherwise.

“Aryl” represents an aromatic carbocyclic group consisting of oneindividual ring, or one or more fused rings in which at least one ringis aromatic in nature. Preferred aryl groups are those having from 6 to10 ring atoms. Preferred aryl group s include phenyl and naphthyl, aswell as those specifically illustrated by the examples herein below.

“Aryloxy” denotes an aryl group as defined hereinabove that is connectedvia an oxygen atom. An example of aryloxy is phenoxy.

“C₁₋₆-alkyl” denotes a straight- or branched-chain hydrocarbon groupcontaining from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl,isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl as well asthose specifically illustrated by the examples herein below.

“Di(C₁₋₆-alkyeamino” denotes a nitrogen atom substituted by twoC₁₋₆-alkyl groups as defined hereinabove. Examples of di(C₁₋₆-alkyeaminoare dimethylamino, diethylamino, dipropylamino, methylethylamino as wellas those groups which are sepcifically illustrated by the examplesherein below.

“Halo” or “Halogen” denotes chlorine, iodine, fluorine and bromine.

“C₁₋₆-haloalkyl” denotes a C₁₋₆-alkyl group as defined above which issubstituted by one or more halogen atom. Examples of C₁₋₆-haloalkylinclude but are not limited to methyl, ethyl, propyl, isopropyl,isobutyl, sec-butyl, tert-butyl, pentyl or n-hexyl substituted by one ormore Cl, F, Br or I atom(s) as well as those groups specificallyillustrated by the examples herein below. Preferred C₁-C₇-haloalkyl aredifluoro- or trifluoro-methyl or ethyl.

“C₁₋₆-alkylsulfonyl” denotes a sulfonyl group (SO₂) which is substitutedby a C₁₋₆-alkyl group as defined above.

“C₁₋₆-alkoxy” denotes an alkyl group as defined above that is connectedvia an oxygen atom.

“C₁₋₆-haloalkoxy” denotes a C₁₋₆-alkoxy group as defined above which issubstituted by one or more halogen atom. Examples of C₁₋₆-haloalkoxyinclude but are not limited to methoxy or ethoxy, substituted by one ormore Cl, F, Br or I atom(s) as well as those groups specificallyillustrated by the examples herein below. Preferred C₁-C₇ haloalkoxy aredifluoro- or trifluoro-methoxy or ethoxy.

The term “lower alkenyl” denotes a straight- or branched-chain carbongroup containing from 2-7, preferably from 2-4, carbon atoms, wherein atleast one bond is a double bond.

The term “thioalkyl” denotes the group —SR wherein R is an alkyl groupas defined above.

“C₃₋₁₀-cycloalkyl” denotes a monovalent saturated cyclic moiety,consisting of one, two or three carbon rings having 3 to 10 carbon atomsas ring members and includes but is not limited to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and polyspiro groupssuch as bicyclo[2.2.2]octanyl, bicyclo[2.2.1]heptanyl,bicyclo[3.2.1]octanyl or adamantanyl as well as those groupsspecifically illustrated by the examples herein below.

The term “thiophenyl” as used herein is synonymous with “thienyl” anddenotes a thiophene substituent, i.e., C₄H₄S.

“5 to 10 membered heteroaryl” means a monocyclic, bicyclic or tricyclicradical of 5 to 10 ring atoms having at least one aromatic ring andfurthermore containing one, two, or three ring heteroatoms selected fromN, O, and S, the remaining ring atoms being C. Heteroaryl can optionallybe substituted with one, two, three or four substituents, wherein eachsubstituent is independently hydroxy, cyano, alkyl, alkoxy, thioalkyl,halo, haloalkyl, hydroxyalkyl, alkoxycarbonyl, amino, acetyl,—NHCOOC(CH₃)₃ or halogen substituted benzyl, or for the non aromaticpart of cyclic ring also by oxo, unless otherwise specificallyindicated. Examples of heteroaryl moieties include, but are not limitedto, optionally substituted imidazolyl, optionally substitutedthiophenyl, optionally substituted oxazolyl, optionally substitutedisoxazolyl, optionally substituted thiazolyl, optionally substitutedpyrazinyl, optionally substituted pyrrolyl, optionally substitutedpyridinyl, optionally substituted pyrimidinyl, optionally substitutedpyridazinyl, optionally substituted indolyl, optionally substitutedisoindolyl, optionally substituted 2,3-dihydroinidolyl, optionallysubstituted indazolyl, optionally substituted naphthyridinyl, optionallysubstituted isoquinolinyl, optionally substituted carbazol-9-yl,optionally substituted furanyl, optionally substituted benzofuranyl,optionally substituted quinolinyl, optionally substitutedbenzo[1,3]dioxolyl, optionally substituted benzo[1,2,3]thiadiazolyl,optionally substituted benzo[b]thiophenyl, optionally substituted9H-thioxanthenyl, optionally substituted thieno[2,3-c]pyridinyl,optionally substituted 3H-imidazo[4,5,b]pyridinyl, optionallysubstituted phthalazinyl, optionally substituted2,3-dihydrobenzo[1,4]dioxinyl, and the like or those which arespecifically exemplified herein.

Preferred 5 to 10 membered heteroaryls are 5 or 6 membered heteroaryls.“4 to 10 heterocycloalkyl” means a monovalent saturated moiety,consisting of one, two or three rings, incorporating one, two, or threeheteroatoms (chosen from nitrogen, oxygen or sulfur). Heterocycloalkylcan optionally be substituted with one, two, three or four substituents,wherein each substituent is independently hydroxy, alkyl, alkoxy,thioalkyl, halo, haloalkyl, hydroxyalkyl, alkoxycarbonyl, amino,alkylamino, dialkylamino, aminocarbonyl, or carbonylamino, unlessotherwise specifically indicated. Examples of heterocyclic moietiesinclude, but are not limited to, piperidinyl, piperazinyl,homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,thiazolidinyl, isothiazolidinyl, quinuclidinyl, quinolinyl,isoquinolinyl, benzimidazolyl, chromanyl, thiadiazolylidinyl,benzothiazolidinyl, benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl,dihydropyranyl, tetrahydropyranyl, thiomorpholinyl, dioxothiomorpholinylthiomorpholinylsulfoxide, thiomorpholinylsulfone, dihydroquinolinyl,dihydrisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,1-oxo-thiomorpholin, 1,1-dioxo-thiomorpholin, 1,4-diazepane,1,4-oxazepane as well as those groups specifically illustrated by theexamples herein below. Preferred 5 to 10 membered heterocycloalkyls are5 or 6 membered heterocycloalkyls.

“One or more” denotes herein, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 andpreferably 1, 2, 3, 4 or 5 and still more preferably 1, 2 or 3.

“Oxo” denotes a group ═O.

Where R³ is the group

R⁸ and R⁹ can form a 3-, 4-, 5-, or 6-membered saturated ring,optionally comprising one or two heteroatoms selected from oxygen andnitrogen and R¹⁰ can be a substituent on the ring formed by R⁸ and R⁹.In such instances R¹⁰ can be, for example, halogen, cyano, hydroxyl,C₁₋₆alkyl, C₁₋₆haloalkyl, and C₁₋₆alkoxy.

“Pharmaceutically acceptable” such as pharmaceutically acceptablecarrier, excipient, salts, etc., means pharmacologically acceptable,generally safe, substantially non-toxic to the subject to which theparticular compound is administered, and neither biologically norotherwise undesirable.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, as defined herein, and that possess thedesired pharmacological activity of the parent compound. Such saltsinclude acid addition salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, benzenesulfonic acid, benzoic, camphorsulfonic acid, citricacid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconicacid, glutamic acid, glycolic acid, hydroxynaphtoic acid,2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,malonic acid, mandelic acid, methanesulfonic acid, muconic acid,2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinicacid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, andthe like.

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

The present invention provides compounds of the general formula (I)

wherein:

-   each X is independently halogen, cyano; C₁₋₆-alkyl, C₁₋₆-alkoxy or    C₁₋₆-haloalkyl;-   n is 0, 1, 2 or 3;-   R¹ is H or C₁₋₆-alkyl;-   R² is

-   R³ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkoxy,    C₃₋₁₀-cycloalkyl, aryl, 4 to 10 membered heterocycloalkyl, or 5 to    10 membered heteroaryl, each of which is optionally substituted by    one to five substituents selected from the group consisting of:    -   halo,    -   cyano,    -   —SO₂—C₁₋₆-alkyl,    -   hydroxy,    -   C₁₋₆-alkyl,    -   C₁₋₆-haloalkyl,    -   —OC(O)—C₁₋₆-alkyl,    -   C₁₋₆-alkoxy optionally substituted by one or more R^(a),    -   C₃₋₁₀-cycloalkyl optionally substituted by one or more R^(a),    -   4 to 10 membered heterocycloalkyl optionally substituted by one        or more R^(a), aryl optionally substituted by one or more R^(a),    -   5 to 10 membered heteroaryl optionally substituted by one or        more R^(a), and —NR^(b)R^(c),        -   wherein R^(b) is H or C₁₋₆-alkyl and wherein R^(a) is H,            C₁₋₆-alkyl or aryl optionally substituted by one or more            R^(a);    -   wherein R^(a) is selected from:        -   halo,        -   cyano,        -   oxo,        -   hydroxy,        -   halobenzenesulfonyl,        -   C₁₋₆-alkyl        -   C₁₋₆-haloalkyl,        -   —NH(CO)—C₁₋₆-alkyl,        -   di(C₁₋₆)alkylamino,        -   —O(CO)—C₁₋₆-alkyl,        -   C₁₋₆-alkylsulfonyl,        -   C₁₋₆-alkoxy        -   C₁₋₆-haloalkoxy,        -   4 to 10 membered heterocycloalkyl        -   aryl,        -   aryloxy, and        -   5 to 10 membered heteroaryl;

as well as pharmaceutically acceptable salts thereof.

Compounds of formula (I) can form acid addition salts with acids, suchas conventional pharmaceutically acceptable acids, for examplehydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate,salicylate, sulphate, pyruvate, citrate, lactate, mandelate, tartarate,and methanesulphonate. Preferred are the hydrochloride salts. Alsosolvates and hydrates of compounds of formula I and their salts formpart of the present invention.

Compounds of formula (I) can have one or more asymmetric carbon atomsand can exist in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates. The opticallyactive forms can be obtained for example by resolution of the racemates,by asymmetric synthesis or asymmetric chromatography (chromatographywith a chiral adsorbens or eluant). The invention embraces all of theseforms.

It will be appreciated, that the compounds of general formula (I) inthis invention can be derivatized at functional groups to providederivatives which are capable of conversion back to the parent compoundin vivo. Physiologically acceptable and metabolically labilederivatives, which are capable of producing the parent compounds ofgeneral formula I in vivo are also within the scope of this invention.

Also encompassed by the compounds of formula (I) are those compoundswherein each X is independently halogen, cyano; C₁₋₆-alkyl, C₁₋₆-alkoxyor C₁₋₆-haloalkyl;

-   n is 0, 1, 2 or 3;-   R¹ is H or C₁₋₆-alkyl;-   R² is

-   R³ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkoxy,    C₃₋₁₀-cycloalkyl, aryl, 4 to 10 membered heterocycloalkyl, or 5 to    10 membered heteroaryl, each of which is optionally substituted by    one to five substituents selected from the group consisting of:    -   halo,    -   hydroxy,    -   C₁₋₆-alkyl,    -   C₁₋₆-haloalkyl,    -   —OC(O)—C₁₋₆-alkyl,    -   C₁₋₆-alkoxy optionally substituted by one or more R^(a),    -   C₃₋₁₀-cycloalkyl optionally substituted by one or more R^(a),    -   4 to 10 membered heterocycloalkyl optionally substituted by one        or more R^(a), aryl optionally substituted by one or more R^(a),    -   5 to 10 membered heteroaryl optionally substituted by one or        more R^(a), and —NR^(b)R^(c),        -   wherein R^(b) is H or C₁₋₆-alkyl and wherein R^(c) is H,            C₁₋₆-alkyl or aryl optionally substituted by one or more            R^(a);    -   wherein R^(a) is selected from:        -   halo,        -   cyano,        -   oxo,        -   hydroxy,        -   halobenzenesulfonyl,        -   C₁₋₆-alkyl        -   C₁₋₆-haloalkyl,        -   —NH(CO)—C₁₋₆-alkyl,        -   di(C₁₋₆)alkylamino,        -   —O(CO)—C₁₋₆-alkyl,        -   C₁₋₆-alkylsulfonyl,        -   C₁₋₆-alkoxy        -   C₁₋₆-haloalkoxy,        -   4 to 10 membered heterocycloalkyl        -   aryl,        -   aryloxy, and

5 to 10 membered heteroaryl;

as well as pharmaceutically acceptable salts thereof.

Also encompassed by the compounds of formula (I) are those compoundswherein each X is independently fluorine or chlorine;

-   n is 0, 1 or 2;-   R¹ is hydrogen;-   R² is

andwherein R³ is as defined hereinabove for formula (I) as well aspharmaceutically acceptable salts thereof.

Also encompassed by the compounds of formula (I) are the compounds offormula (Ia)

wherein

-   each X is independently fluorine or chlorine;-   n is 0, 1 or 2;-   m is 0, 1, 2 or 3;-   R⁴ is selected from the group consisting of:    -   halo,    -   cyano,    -   hydroxy,    -   C₁₋₆-alkyl,    -   C₁₋₆-haloalkyl,    -   di(C₁₋₆)alkylamino,    -   —OC(O)—C₁₋₆-alkyl,    -   C₁₋₆-alkoxy optionally substituted by one or more R^(a),    -   C₃₋₁₀-cycloalkyl optionally substituted by one or more R^(a),    -   4 to 10 membered heterocycloalkyl optionally substituted by one        or more R^(a), aryl optionally substituted by one or more R^(a),    -   5 to 10 membered heteroaryl optionally substituted by one or        more R^(a), and —NR^(b)R^(c),        wherein R^(a), R^(b) and R^(a) are as defined hereinabove for        formula (I) as well as pharmaceutically acceptable salts        thereof.

Preferred compounds of formula (Ia) are the compounds wherein

each X is independently fluorine or chlorine;

n is I;

m is 0, 1 or 2;R⁴ is selected from the group consisting of:

-   -   halo,    -   C₁₋₆-alkoxy optionally substituted by one or more R^(a),    -   6 membered heterocycloalkyl optionally substituted by one or        more R^(a), and    -   5 to 6 membered heteroaryl optionally substituted by one or more        R^(a),        wherein R^(a) is selected from    -   halo,    -   oxo,    -   hydroxyl and    -   C₁₋₆-alkyl,        as well as pharmaceutically acceptable salts thereof.

Especially preferred compounds of formula (Ia) are for example thefollowing compounds:

-   3-Fluoro-N-trans    (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide,-   N-trans (4-{2-[4-(6    Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-methoxy-benzamide-   4-tert-Butoxy-N-trans    (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide,-   4-Chloro-N-trans    (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide,-   N-trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-pyrrol-1-yl-benzamide,-   Benzo[1,3]dioxole-5-carboxylic acid trans    (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,    and-   Benzo[1,3]dioxole-5-carboxylic acid trans    (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide.

Also encompassed by the compounds of formula (I) are the compounds offormula (Ib):

wherein

each X is fluorine or chlorine;

n is 0, 1 or 2;

m and p are each independently 0, 1 or 2;

R⁴ and R⁵ are each independently selected from the group consisting of:

-   -   halo,    -   cyano,    -   hydroxy,    -   C₁₋₆-alkyl,    -   C₁₋₆-haloalkyl,    -   —OC(O)—C₁₋₆-alkyl,    -   C₁₋₆-alkoxy optionally substituted by one or more R^(a),    -   C₃₋₁₀-cycloalkyl optionally substituted by one or more R^(a),    -   4 to 10 membered heterocycloalkyl optionally substituted by one        or more R^(a),    -   aryl optionally substituted by one or more R^(a),    -   5 to 10 membered heteroaryl optionally substituted by one or        more R^(a),    -   and    -   —NR^(b)R^(c),        wherein R^(a), R^(b) and R^(c) are as defined in claim 1;        Y is oxygen or —SO₂—;        one, two or three of A¹, A², A³, A⁴ and A⁵ are nitrogen and the        others are CR⁶, or A¹, A², A³, A⁴ and A⁵ are CR⁶ wherein        each R⁶ is independently hydrogen or R⁷; and        each R⁷ is independently C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyl,        amino, C₁₋₆alkylamino, N,N-di-(C₁₋₆alkyl)-amino, halo,        halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, hetero-C₁₋₆alkyl,        C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfanyl, or cyano; as well as        pharmaceutically acceptable salts thereof.

Preferred compounds of formula (Ib) are the compounds wherein

X is fluorine;n and m are each independently 0 or 1;p is 0;R⁴ is selected from the group consisting of:

halo,

cyano,

hydroxy,

C₁₋₆-alkyl, and

C₁₋₆-haloalkyl,

Y is oxygen or —SO₂—;one or two of A¹, A², A³, A⁴ and A⁵ are nitrogen and the others are CH₂;

as well as pharmaceutically acceptable salts thereof.

Especially preferred compounds of formula (Ib) are for example thefollowing compounds:

-   N-trans (4-{2-[4-(6    Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide,-   N-trans    (4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide,-   N-Trans    (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-6-morpholin-4-yl-nicotinamide,-   5-Morpholin-4-yl-pyrazine-2-carboxylic acid trans    (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,-   6-Morpholin-4-yl-pyridazine-3-carboxylic acid-trans    (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,-   2-Morpholin-4-yl-pyrimidine-5-carboxylic acid trans    (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,-   3-Fluoro-N-trans    (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide,-   4-(1,1-Dioxo-1,6-thiomorpholin-4-yl)-N-trans    (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide,-   N-trans    (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-morpholin-4-yl-isonicotinamide,-   N-trans    (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-piperidin-1-yl-benzamide,-   N-trans    (4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-piperidin-1-yl-benzamide,-   4-(2,6-Dimethyl-morpholin-4-yl)-N-trans    (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide,-   4-(2,6-Dimethyl-morpholin-4-yl)-N-trans    (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide,    and-   4-(1,1-Dioxo-1,6,4-thiomorpholin-4-yl)-N trans (4-{2-[4-(5    fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide.

Also encompassed by the compounds of formula (I) are the compounds offormula (Ic):

whereineach X is independently fluorine or chlorine;n is 0, 1 or 2;R⁸ and R⁹ form a 3-, 4-, 5-, or 6-membered saturated ring, optionallycomprising one or two heteroatoms selected from oxygen and nitrogen;R¹⁰ can be a substituent on the ring formed by R⁸ and R⁹ and is selectedfrom the group consisting of

halogen,

cyano,

hydroxy,

C₁₋₆-alkyl,

C₁₋₆-haloalkyl and

C₁₋₆-alkoxy;

as well as pharmaceutically acceptable salts thereof.

Also encompassed by the compounds of formula (I) are the compounds offormula (Id):

wherein

-   -   X₁=H and X₂=fluoro or chloro; or    -   X₂═H and X₁=fluoro or chloro; and    -   R¹¹ is selected from the group consisting of C₁₋₆-alkyl and        C₁₋₆-alkoxy, each of which is optionally substituted by halogen,        hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy or        C₅₋₆-cycloalkyl which is optionally substituted by C₁₋₆-alkyl or        C₁₋₆-alkoxy;        as well as pharmaceutically acceptable salts thereof.

Special preference is given to the compounds of formula (Id′):

wherein X₁, X₂, and R¹¹ are as defined hereinabove for formula (Id) aswell as pharmaceutically acceptable salts thereof.

Especially preferred compounds of formula (Id′) are for example thefollowing compounds:

-   4N-trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide,-   Tetrahydro-pyran-4-carboxylic acid trans    (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,-   N-trans    (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,-   N-trans    (4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide,-   N-trans    (4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,-   Trans    4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine,-   2,3-Dihydro-benzo[1,4]dioxine-2-carboxylic acid trans    (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,-   N-trans    (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(3-methyl-pyrazol-1-yl)-acetamide,-   3,3,3-Trifluoro-N-trans    (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-propionamide,-   2-(3,5-Dimethoxy-phenyl)-N-trans    (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide,-   N-trans    (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,-   N-trans    (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide,-   N-trans (4-{2-[4-(6    Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3,3,3-trifluoro-2-hydroxy-propionamide,-   N-trans    (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-pyran-2-yl)-acetamide,-   N-trans (4-{2-[4-(6    Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-trans    (4-methoxy-cyclohexyl)-acetamide,-   N-trans    (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(1,4-dioxa-spiro[4.5]dec-8-yl)-acetamide,    and-   N-trans (4-{2-[4-(6    Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3,3-dimethoxy-propionamide.

Also encompassed by the compounds of formula (I) are the compounds offormula (Ie):

wherein

X₁═H and X₂=fluoro or chloro; or

X₂═H and X₁=fluoro or chloro; and

R¹² is selected from the group consisting of

-   -   halo,    -   hydroxy,    -   cyano,    -   C₁₋₆-alkyl,    -   C₁₋₆-haloalkyl and    -   C₁₋₆-alkoxy;

as well as pharmaceutically acceptable salts thereof.

Special preference is given to the compounds of formula (Ie′):

wherein X₁, X₂, and R¹² are as defined hereinabove for formula (Ie) aswell as pharmaceutically acceptable salts thereof.

Especially preferred compounds of formula (Ie′) are for example thefollowing compounds:

-   1-Hydroxy-cyclopropanecarboxylic acid trans    (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,    and-   1-Trifluoromethyl-cyclobutanecarboxylic acid trans    (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide.

Also encompassed by the compounds of formula (I) are the compounds offormula (Ig):

wherein

each X is independently fluorine or chlorine;

n is 0, 1 or 2;

R¹³ is selected from the group consisting of

C₁₋₆-alkyl,

C₁₋₆-haloalkyl,

C₁₋₆-alkoxy,

aryl optionally substituted by one or more R^(a), and

5 to 10 membered heteroaryl optionally substituted by one or more R^(a);

R^(a) is halo, C₁₋₆-alkyl or C₁₋₆-alkoxy;

as well as pharmaceutically acceptable salts thereof.

Especially preferred compounds of formula (Ig) are for example thefollowing compounds:

-   Ethanesulfonic acid (4-trans    {2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,-   4-Chloro-N-trans    (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzenesulfonamide,-   N-trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-methoxy-benzenesulfonamide,    and-   Pyridine-3-sulfonic acid    trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide.

Special preference is also given to the following compounds:

-   N-trans (4-{2-[4-(6    Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-cyano-propionamide,-   N-trans (4-{2-[4-(6    Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-cyano-acetamide,-   N-trans (4-{2-[4-(6    Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(R)-tetrahydro-furan-2-yl-acetamide,-   N-trans (4-{2-[4-(6    Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-cyclopropyl-acetamide,-   N-trans (4-{2-[4-(6    Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-hydroxy-acetamide,-   N-trans (4-{2-[4-(6    Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-methanesulfonyl-acetamide,-   N-trans (4-{2-[4-(6    Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-[1,3]dioxan-2-yl-acetamide,-   N-trans (4-{2-[4-(5    Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-cyclohexyl)-acetamide,-   N-trans (4-{2-[4-(5    Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-methanesulfonamide,-   N-trans (4-{2-[4-(6    Chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,-   N-trans (4-{2-[4-(6    Chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-furan-2-yl)-acetamide,-   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-methoxy-acetamide,-   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-((1R,3R)-3-methoxy-cyclopentyl)-acetamide,-   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-cyclohexyl)-acetamide,-   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,-   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide,-   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-hydroxy-acetamide,-   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-hydroxy-propionamide,-   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-hydroxy-cyclohexyl)-acetamide,-   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-((1R,3R)-3-hydroxy-cyclopentyl)-acetamide,-   Tetrahydro-pyran-4-carboxylic acid    trans-(4-{2-[4-(5,6-difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,-   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-[1,3]dioxan-2-yl-acetamide,    and-   N-trans (4-{2-[4-(6    Methyl-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide.

A further aspect of the present invention relates to pharmaceuticalcompositions containing the compounds of formulae (I), (Ia), (Ib), (Ic),(Id) (Id′), (Ie), (Ie′) and (Ig) and a pharmaceutically acceptablecarrier.

In a further aspect the present invention provides processes for themanufacture of compounds of formula (I) as defined above.

The preparation of compounds of formula (I) of the present invention canbe carried out in sequential or convergent synthetic routes. Synthesesof the invention are shown in the following schemes. The skills requiredfor carrying out the reaction and purification of the resulting productsare known to those skilled in the art. The substituents and indices usedin the following description of the processes have the significancegiven herein before unless indicated to the contrary.

In more detail, the compounds of formula (I) can be manufactured by themethods given below, by the methods given in the examples or byanalogous methods. Appropriate reaction conditions for the individualreaction steps are known to a person skilled in the art. Startingmaterials are either commercially available or can be prepared bymethods analogous to the methods given below, by methods described inreferences cited in the description or in the examples, or by methodsknown in the art.

4-(benzo-isoxazol-3-yl)-piperidin-1-yl trans-ethyl-cyclohexyl-amides ortrans-1,4-cyclohexyl ethyl derivates of formula IA can be prepared asdepicted in scheme 1 starting from 4-nitro-phenylacetic acid that washydrogenated using raney nickel as a catalyst. The hydrogenation withnickel leads preferentially to the desired trans-isomer (according toJournal of Medicinal Chemistry, 1998, 41, 760-771). The ethyl ester canbe prepared according to methods known to those skilled in the art anddescribed in the mentioned literature (e.g by treatment with ethanol onthe presence of an acid such as HCl). The HCl salt can be crystallizedand then the cis/trans mixture can be resolved into the pure trans aminoester chloride B. Reaction with a protecting group such as tert-butyldicarbonate in the presence of a base, like triethylamine, and acatalyst, like dimethylaminopyridine, and reduction withdiisobutylaluminium hydride (DIBAL-H) in an appropriate solvent, e.g.toluene at −78° C. gave the aldehyde C which can be used withoutpurification in the next step. Reductive amination of aldehyde C with asubstituted 4-(benzo[d]isoxazol-3-yl)-piperidine D can be performedusing methods described in the literature, by methods described hereinor by methods known in the art. The reductive amination can take placein the presence of a solvent, like 1,2-Dichloromethane, and/or areducing agent, such as sodium triacetoxy borohydride, to yieldintermediate E. Removal of the Boc protective group under acidicconditions, such as trifluoroacetic acid, in a suitable solvent, e.g.THF, yields the trans-amino cyclohexyl ethyl intermediate F (usually theTFA salt). The coupling of the amine intermediate F with carboxylicacids (either commercially available or accessible by methods describedin references or by methods known in the art) is widely described inliterature (e.g. Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 2nd Edition, Richard C. Larock. JohnWiley & Sons, New York, N.Y. 1999) and can be accomplished by employingcoupling reagents such as, e.g. N,N-carbonyldiimidazole (CDI),1-hydroxy-1,2,3-benzotriazole (HOBT) orO-benzotriazol-1-yl-N,N,N,N-tetramethyluronium tetrafluoroborate (TBTU)in a suitable solvent, e.g. dimethylformamide (DMF) or dioxane, in thepresence of a base (e.g. triethylamine or diisopropylethylamine) toyield compounds of formula IA. In other cases an acid chloride can alsobe used in the presence of a base (e.g. triethylamine ordiisopropylethylamine) in a solvent, like dichloromethane.

Some substituted 4-(benzo[d]isoxazol-3-yl) -piperidines of formula D canbe obtained by Friedel-Crafts acylation of an adequate benzenederivative using an appropriate Lewis acid, like alumminium chloride, inthe presence of 1-acetylisonipecotoyl chloride in a solvent, likedichlorobenzene, by heating to a temperature of about 70° C. asdescribed in Journal of Medicinal Chemistry, 1985, 28, 761-769; Journalof Medicinal Chemistry, 1970, 13, 1-6; or U.S. Pat. No. 4,355,037.

Alternatively 4-(benzo[d]isoxazol-3-yl)-piperidines of formula D can beobtained starting from an appropriately substituted benzaldehydecontaining a leaving group such as for example F in the ortho position(in analogy to WO02066446). The benzaldehyde can be converted to adimethyl acetal with a reagent, such as trimethyl orthoformiate, in thepresence a catalytic amount of an acid, such as pTsOH. Reaction of theacetal with triethylorthophosphite in presence of a Lewis acid, such asTiC14, in a solvent, such as CH₂Cl₂, leads to a phosphonate that can bedeprotonated with a base, such as nBuLi, in a solvent, like THF, andreacted with 1-benzyl-piperidin-4-one to obtain an enol ether asdepicted in Scheme 2B. Treatment of the enol ether with an acid, such asconcentrated aqueous HCl, in a solvent, such as acetone, yields thecorresponding ketone. Reaction of the ketone with NH₂OH.HCl in thepresence of a base, such as DIPEA, in a solvent, like EtOH, followed bydeprotonation of the oxime with a base, such as KOtBu, in THF andintramolecular cyclization leads to the benzo[d]isoxazole derivative.The 4-(benzo[d]isoxazol-3-yl)-piperidines of formula D are then obtainedby debenzylation employing methods known in the art, for examplereaction with α-chloroethyl chloroformate and subsequent treatment withrefluxing MeOH.

In other examples the intermediate F can also react with a sulfonylchloride in the present of a base, like triethylamine, to give thecorresponding sulfonyl derivative of the formula IA.

The ability of the compounds to bind to the 5-HT_(2A), D3 and D2receptors was determined using radioligand binding to cloned receptorsselectively expressed in HEK-293 EBNA cells.

Membrane Preparation for Human D₂, Human D₃ and Human 5-HT_(2A)Receptors

HEK-293 EBNA cells were transiently transfected with expression plasmidsencoding for the human D₂ or D₃ dopamine- or for the human 5-HT_(2A)serotonin receptor, respectively. The cells were harvested 48 hpost-transfection, washed three times with cold PBS and stored at −80°C. prior to use. The pellet was suspended in cold 50 mM Tris-HCl buffercontaining 10 mM EDTA (pH 7.4) and homogenized with a Polytron(Kinematica AG, Basel, Switzerland) for 20-30 sec at 12,000 rpm. Aftercentrifugation at 48,000×g for 30 min at 4° C., the pellet wasresuspended in cold 10 mM Tris-HCl buffer containing 0.1 mM EDTA (pH7.4), homogenized, and centrifuged as above. This pellet was furtherresuspended in a smaller volume of ice cold 10 mM Tris-HCl buffercontaining 0.1 mM EDTA (pH 7.4) and homogenized with a Polytron for20-30 sec at 12,000 rpm. The protein content of this homogenate wasdetermined with the Bio-Rad (Bradford) Protein Assay (BioradLaboratories GmbH, Munchen, Germany) according to the instructions ofthe manufacturer using gamma globulin as the standard. This homogenatewas stored at −80° C. in aliquots and thawed immediately prior to use.

Radioligand Binding Assay Conditions

Aliquots of membrane preparations were thawed at RT, resupended in assaybuffer (D2, D₃: 50 mM Tris-HCl, 120 mM NaCl, 5 mM MgCl₂, 1 mM EDTA, 5 mMKCl, 1.5 mM CaCl₂, pH=7.4; 5-HT_(2A): 50 mM Tris-HCl, 10 mM MgCl₂, 1 mMEGTA, pH=7.4), homogenized with a Polytron for 20-30 sec at 12,000 rpmand adjusted to a final concentration of approximately 7.5 μgprotein/well (D₂, D₃) and 15 μg protein/well (5-HT_(2A)), respectively.

The binding affinity (Ki) of the compounds was determined usingradioligand binding. Membranes were incubated in a total volume of 200μl with a fixed concentration of radioligand (final concentrationapproximately 0.7 nM [³H]-spiperone for D₂, 0.5 nM [³H]-spiperone forD₃, and 1.1 nM [³H]-ketanserin for 5-HT_(2A)) and ten concentrations oftest compound in ranging between 10 μM-0.1 nM for 1 h at RT. At the endof the incubation, the reaction mixtures were filtered on to unifilter96-well white microplates with bonded GF/C filters (Packard BioScience,Zurich, Switzerland; preincubated for 1 h in 0.1% polyethylenimine (PEI)in assay buffer) with a Filtermate 196 harvester (Packard BioScience)and washed 3 times with cold assay buffer. The nonspecific binding wasdetermined with equally composed reaction mixtures in the presence of 10μM unlabelled spiperone. Per well 45 μl of Microscint 40 (Perkin Elmer,Schwerzenbach, Switzerland) was added, plates for sealed, shaken for 20min and counted for 3 min on a Topcount Microplate Scintillation Counter(Can berra Packard SA, Zurich, Switzerland) with quenching correction.

Data Calculation

The CPM value for each duplicate of a concentration of competingcompound was averaged (y1), then the % specific binding was calculatedaccording to the equation (((y1−non-specific)/(totalbinding−non-specific))×100). Graphs were plotted with the % specificbinding using XLfit, a curve fitting program that iteratively plots thedata using Levenburg Marquardt algorithm. The single site competitionanalysis equation used was y=A+((B−A)/(1+((x/C)^(D)))), where y is the %specific binding, A is the minimum y, B is the maximum y, C is the IC₅₀,x is the log₁₀ of the concentration of the competing compound and D isthe slope of the curve (the Hill Coefficient). From these curves theIC₅₀ (inhibition concentration at which 50% specific binding of theradioligand was displaced) and Hill coefficient were determined. Theaffinity constant (Ki) was calculated using the Cheng-Prusoff equationKi=(IC₅₀/1+([L]/Kd), where [L] is the concentration of radioligand andKd is the dissociation constant of the radioligand at the receptor asdetermined by the saturation isotherm.

The compounds of the present invention are selective dual modulators ofthe serotonin 5-HT2a and dopamine D3 receptors as shown in the activitytable hereinafter which gives the Ki values in μM for the serotonin5-HT_(2a), dopamine D₃ and dopamine D₂ receptors for some examples ofthe compounds of the present invention:

ACTIVITY TABLE Ki dopa- Ki mine d3 5-HT_(2a): receptor: Human human Ex.Compound Name (5HT2a) (D3)  1

4N-trans(4-{2-[4- (6-Fluoro- benzo[d]isoxazol-3- yl)-piperidin-1-yl]-ethyl}-cyclohexyl)- acetamide 0.002224 0.004964  2

Tetrahydro-pyran-4- carboxylic acid trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}- cyclohexyl)-amide0.001739 0.009744  3

N-trans (4-{2-[4-(6- Fluoro-benzo[d]isoxazol- 3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3- methoxy-propionamide 0.001809 0.004749  4

N-trans-(4-{2-[4-(6- Fluoro-benzo[d]isoxazol- 3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4- morpholin-4-yl- benzamide 0.009519 0.028161  4A

N-Trans (4-{2-[4-(6- Fluoro-benzo[d]isoxazol- 3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-6- morpholin-4-yl- nicotinamide 0.002701 0.007948  4B

5-Morpholin-4-yl- pyrazine-2-carboxylic acid trans (4- {2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}- cyclohexyl)-amide0.00381 0.019443  4C

6-Morpholin-4-yl- pyridazine-3-carboxylic acid-trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol- 3-yl)-piperidin-1-yl]- ethyl}-cyclohexyl)-amide 0.003181 0.025326  4D

2-Morpholin-4-yl- pyrimidine-5-carboxylic acid trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol- 3-yl)-piperidin-1-yl]- ethyl}-cyclohexyl)-amide 0.002453 0.01534  5

3-Fluoro-N-trans (4-{2- [4-(6-fluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-4- morpholin-4-yl- benzamide 0.017460.045277  6

3-Fluoro-N-trans (4-{2- [4-(6-fluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-4- morpholin-4-yl- benzamide0.011383 0.01152  7

Trans 4-{2-[4-(6-Fluoro- benzo[d]isoxazol- 3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine (could be obtained as the trifluoroacetic acidsalt) and 3,4- (methylenedioxy) phenylacetic acid 0.002087 0.004015  8

N-trans-(4-{2-[4-(6- Fluoro- benzo[d]isoxazol- 3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4- methoxy-benzamide 0.003654 0.004525  9

4-tert-Butoxy-N-trans (4-{2-[4-(6-fluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-benzamide 0.001724 0.003417 10

4-Chloro-N-trans (4-{2- [4-(6-fluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-benzamide 0.002666 0.003498 11

4-(1,1-Dioxo-1,6- thiomorpholin-4-yl)-N- trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}- cyclohexyl)-benzamide0.002483 0.004674 12

N-trans (4-{2-[4-(6- Fluoro- benzo[d]isoxazol- 3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2- morpholin-4-yl- isonicotinamide 0.002459 0.00574713

N-trans (4-{2-[4-(6- Fluoro- benzo[d]isoxazol- 3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2- methoxy- isonicotinamide 0.001623 0.003738 14

N-trans (4-{2-[4- (6-Fluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-4-piperidin- 1-yl-benzamide 0.0025980.008685 15

2,3-Dihydro- benzo[1,4]dioxine-2- carboxylic acid trans (4-{2-[4-(6-fluoro- benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}-cyclohexyl)-amide 0.00257 0.01266 16

N-trans (4-{2-[4- (6-Fluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2-(3- methyl-pyrazol-1-yl)-acetamide 0.002795 0.027618 17

N-trans (4-{2-[4- (6-Fluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-4-pyrrol-1- yl-benzamide 0.002450.002607 18

1-Hydroxy- cyclopropanecarboxylic acid trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol- 3-yl)-piperidin-1-yl]- ethyl}-cyclohexyl)-amide 0.001444 0.005916 19

1-Trifluoromethyl- cyclobutanecarboxylic acid trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol- 3-yl)-piperidin-1-yl]- ethyl}-cyclohexyl)-amide 0.002257 0.00774 20

3,3,3-Trifluoro-N-trans (4-{2-[4-(6-fluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)- propionamide 0.002782 0.005189 21

2-(3,5-Dimethoxy- phenyl)-N-trans (4-{2- [4-(6-fluoro-benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}- cyclohexyl)-acetamide0.002953 0.008772 22

4-(2,6-Dimethyl- morpholin-4-yl)-N-trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}- cyclohexyl)-benzamide0.021224 0.136625 23

Benzo[1,3]dioxole-5- carboxylic acid trans (4- {2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}- cyclohexyl)-amide0.001714 0.002746 24

N-trans (4-{2-[4- (5-Fluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-acetamide 0.046865 0.002438 25

N-trans (4-{2-[4-(5- Fluoro- benzo[d]isoxazol- 3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4- morpholin-4-yl- benzamide 0.02232 0.009036 26

N-trans (4-{2-[4-(5- Fluoro- benzo[d]isoxazol- 3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3- methoxy- propionamide 0.036954 0.003099 27

N-trans (4-{2-[4-(5- Fluoro- benzo[d]isoxazol- 3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4- piperidin-1-yl- benzamide 0.007004 0.0077 28

4-(2,6-Dimethyl- morpholin-4-yl)-N-trans (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}- cyclohexyl)-benzamide0.099138 0.085773 29

4-(1,1-Dioxo-1,6,4- thiomorpholin-4-yl)-N- trans-(4-{2-[4-(5- fluoro-benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}- cyclohexyl)-benzamide0.012352 0.005936 30

Benzo[1,3]dioxole-5- carboxylic acid trans (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}- cyclohexyl)-amide0.011217 0.003861 32

N-trans (4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-3-methoxy- propionamide 0.016550.008497 33

N-trans-(4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-3,3,3- trifluoro-2-hydroxy-propionamide 0.021866 0.011029 34

N-trans (4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2- (tetrahydro-pyran-2-yl)-acetamide 0.005829 0.010734 34A

N-trans (4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2-(R)- tetrahydro-pyran-2-yl-acetamide 0.01368 0.010734 34B

N-trans (4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2-(S)- tetrahydro-pyran-2-yl-acetamide 0.015304 0.003708 35

N-trans-(4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2-trans (4- methoxy-cyclohexyl)-acetamide 0.009637 0.011578 36

N-trans (4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2-(1,4- dioxa-spiro[4.5]dec-8-yl)-acetamide 0.00831 0.012221 37

N-trans-(4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-3,3- dimethoxy- propionamide 0.013650.00903 38

N-trans-(4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2- (tetrahydro-furan-2-yl)-acetamide 0.013 0.009 39

(R)-N-trans (4-{2-[4- (6-Chloro- benzo[d]isoxazol-3- yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-3- hydroxy-butyramide 0.013 0.017 40

N-trans (4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2-((S)-2,2- dimethyl- [1,3]dioxolan-4-yl)-acetamide 0.025 0.006 41

N-trans (4-{2-[4-(6- Chloro- benzo[d]isoxazol-3- yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2- ((1S,3S)-3-methoxy- cyclopentyl)-acetamide 0.0140.010 42

N-trans (4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2-(4- methoxy-4-methyl-cyclohexyl)-acetamide 0.019 0.008 42A

N-trans (4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2-(4-trans- methoxy-4-methyl-cyclohexyl)-acetamide 0.016 0.006 42B

N-trans (4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2-(4-cis- methoxy-4-methyl-cyclohexyl)-acetamide 0.014 0.004 43

N-trans (4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-3- methoxy-butyramide 0.013 0.01043A

(R)-N-trans (4-{2-[4- (6-Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-3- methoxy-butyramide 0.016 0.01543B

(S)-N-(4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-3- methoxy-butyramide 0.016 0.006 44

N-trans-(4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2-trans (4- methoxymethyl-cyclohexyl)-acetamide 0.019 0.009 45

N-trans (4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2-(4- hydroxy-4-methyl-cyclohexyl)-acetamide 0.015 0.007 46

N-trans (4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-acetamide 0.023745 0.008189 47

Ethanesulfonic acid (4- trans {2-(4-(6-fluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-amide 0.001664 0.005852 48

4-Chloro-N-trans (4- {2-[4-(6-fluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)- benzenesulfonamide 0.0051320.005867 49

N-trans(4-{2-[4-(6- Fluoro- benzo[d]isoxazol- 3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4- methoxy- benzenesulfonamide 0.004394 0.003719 50

Pyridine-3-sulfonic acid trans(4-{2-[4-(6- fluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]- ethyl}-cyclohexyl)- amide 0.002476 0.00195 51

N-trans-(4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-3-cyano- propionamide 0.0237450.008189 52

N-trans-(4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2-cyano- acetamide 0.015582 0.00877253

N-trans-(4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2-(R)- tetrahydro-furan-2-yl-acetamide 0.006193 0.014446 54

N-trans-(4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2- cyclopropyl-acetamide 0.0130920.003206 55

N-trans-(4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2- hydroxy-acetamide 0.0149910.01681 56

N-trans-(4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2- methanesulfonyl- acetamide0.015216 0.014784 57

N-trans-(4-{2-[4-(6- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2- [1,3]dioxan-2-yl- acetamide0.017625 0.00613 58

N-trans-(4-{2-[4-(5- Chloro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2-(4- methoxy-cyclohexyl)- acetamide0.02467 0.008381 59

N-trans-(4-{2-[4-(5- Fluoro- benzo[d]isoxazol- 3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)- methanesulfonamide 0.027483 0.00798 60

N-trans-(4-{2-[4-(6- Chloro-5-fluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-3- methoxy-propionamide 0.0439680.01354 61

N-trans-(4-{2-[4-(6- Chloro-5-fluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2- (tetrahydro-furan-2-yl)-acetamide 0.031001 0.017732 62

N-trans-(4-{2-[4-(5,6- Difluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2- methoxy-acetamide 0.010520.032674 63

N-trans-(4-{2-[4-(5,6- Difluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2- ((1R,3R)-3-methoxy-cyclopentyl)-acetamide 0.013209 0.019994 64

N-trans-(4-{2-[4-(5,6- Difluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2-(4- methoxy-cyclohexyl)- acetamide0.00767 0.017303 65

N-trans-(4-{2-[4-(5,6- Difluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-3- methoxy-propionamide 0.0129180.011356 66

N-trans-(4-{2-[4-(5,6- Difluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-acetamide 0.017739 0.011368 67

N-trans-(4-{2-[4-(5,6- Difluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2-hydroxy- acetamide 0.0117820.01995 68

N-trans-(4-{2-[4-(5,6- Difluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-3- hydroxy-propionamide 0.0247920.01172 69

N-trans-(4-{2-[4-(5,6- Difluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2-(4- hydroxy-cyclohexyl)- acetamide0.007848 0.020912 70

N-trans-(4-{2-[4-(5,6- Difluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2-((1R,3R)- 3-hydroxy- cyclopentyl)-acetamide 0.011439 0.019756 71

Tetrahydro-pyran-4- carboxylic acid trans- (4-{2-[4-(5,6- difluoro-benzo[d]isoxazol- 3-yl)-piperidin-1- yl]-ethyl}- cyclohexyl)-amide0.00786 0.018169 72

N-trans-(4-{2-[4-(5,6- Difluoro- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-2- [1,3]dioxan-2-yl- acetamide0.009394 0.013512 73

N-trans-(4-{2-[4-(6- Methyl- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- cyclohexyl)-acetamide 0.016758 0.009275

The present invention also provides pharmaceutical compositionscontaining compounds of the invention, for example, compounds of formulaI or pharmaceutically acceptable salts thereof and a pharmaceuticallyacceptable carrier. Such pharmaceutical compositions can be in the formof tablets, coated tablets, dragées, hard and soft gelatin capsules,solutions, emulsions or suspensions. The pharmaceutical compositionsalso can be in the form of suppositories or injectable solutions.

The pharmaceutical compositions of the invention, in addition to one ormore compounds of the invention, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic or organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts and thelike can be used, for example, as such as carriers for tablets, coatedtablets, dragées and hard gelatine capsules. Suitable carriers for softgelatine capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like; depending on the nature ofthe active substance no carriers are, however, usually required in thecase of soft gelatine capsules. Suitable carriers for the production ofsolutions and syrups are, for example, water, polyols, sucrose, invertsugar, glucose and the like. Adjuvants, such as alcohols, polyols,glycerol, vegetable oils and the like, can be used for aqueous injectionsolutions of water-soluble salts of compounds of formula I, but as arule are not necessary. Suitable carriers for suppositories are, forexample, natural or hardened oils, waxes, fats, semi-liquid or liquidpolyols and the like.

In addition, the pharmaceutical compositions can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

The present invention also provides a method for the manufacture ofpharmaceutical compositions. Such process comprises bringing one or morecompounds of formula I and/or pharmaceutically acceptable acid additionsalts thereof and, if desired, one or more other therapeuticallyvaluable substances into a galenical administration form together withone or more therapeutically inert carriers.

The compounds and compositions of the present invention can beadministered in a conventional manner, for example, orally, rectally, orparenterally. The pharmaceutical compositions of the invention can beadministered orally, for example, in the form of tablets, coatedtablets, dragées, hard and soft gelatine capsules, solutions, emulsions,or suspensions. The pharmaceutical compositions also can be administeredrectally, for example, in the form of suppositories, or parenterally,for example, in the form of injectable solutions.

As mentioned hereinabove, the compounds of the invention have highaffinity for the dopamine D₃ and serotonin 5-HT_(2A) receptors and areexpected to be effective in the treatment of psychotic disorders whichinclude schizophrenia, schizoaffective disorders, bipolar disease,mania, psychotic depression, and other psychoses involving paranoia anddelusions (Reavill-C, et al. (2000) Pharmacological actions of a novel,high-affinity, and selective human dopamine D3 receptor antagonist,SB-277011-A. JPET 294:1154-1165; Harrison, P. J. (1999) Neurochemicalalterations in schizophrenia affecting the putative receptor targets ofatypical antipsychotics.

Focus on dopamine (D1, D3, D4) and 5-HT_(2A) receptors. Br. J.Psychiatry Suppl. 38, 12-22; de Angelis, L. (2002) 5-HT_(2A) antagonistsin psychiatric disorders. Curr. Opin. Investig. Drugs 3, 106-112; Joyce,J. N. and Millan, M. J., (2005) Dopamine D3 receptor antagonists astherapeutic agents. Drug Discovery Today, 1 July, Vol. 10, No. 13, P.917-25); drug dependency and abuse and withdrawal (Vorel, S. R. et al.(2002) Dopamine D3 receptor antagonism inhibits cocaine-seeking andcocaine-enhanced brain reward in rats. J. Neurosci., 22, 9595-9603;Campos, A. C. et al. (2003) The dopamine D3 receptor antagonistSB277011A antagonizes nicotine-enhanced brain-stimulation reward in rat.Soc. Neurosci. Abstr., 322.8; Ashby, et al. (2003) Acute administrationof the selective D3 receptor antagonist SB-277011-A blocks theacquisition and expression of the conditioned place preference responseto heroin in male rats. Synapse, 48, 154-156); anxiety, and depression(Reavill-C et al. (2000) Pharmacological actions of a novel,high-affinity, and selective human dopamine D3 receptor antagonist,SB-277011-A. JPET 294:1154-1165; Drescher, K. et al. (2002) In vivoeffects of the selective dopamine D3 receptor antagonist A-437203. Am.Soc. Neurosci. 894.6).

The dosage at which compounds of the invention can be administered canvary within wide limits and will, of course, be fitted to the individualrequirements in each particular case. In general, the effective dosagefor oral or parenteral administration is between 0.01-20 mg/kg/day, witha dosage of 0.1-10 mg/kg/day being preferred for all of the indicationsdescribed. The daily dosage for an adult human being weighing 70 kgaccordingly lies between 0.7-1400 mg per day, preferably between 7 and700 mg per day.

The following examples are provided to further elucidate the invention:

Example 1 4N-trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamideIntermediate B Trans-(4-amino-cyclohexyl)-acetic acid ethyl ester Step 1

(4-Nitro-phenyl)-acetic acid (50 g, 276 mmol) was added to a stirredsolution of 22.08 g of 50% sodium hydroxide solution in 450 mLdeionizated water. The clear yellow solution is transferred into ahigh-pressure autoclave that it charged with 30 g (511 mmol) ofwater-wet sponge nickel catalyst. The autoclave is sealed, flushed withnitrogen and then pressurized to 115 bar with hydrogen. The reactionmixture is stirred and heated to 125° C. for 48 h. At that time theautoclave is cooled, vented and charged under nitrogen with another 30 g(511 mmol) of the sponge nickel catalyst. The autoclave is flushed againwith nitrogen and then pressurized to 115 bar and the vessel is heatedto 130° C. while stirring (a maximum pressure of 130 bars is observed).Hydrogenation is continued for 5 days to 130° C. The autoclave is thencooled, vented and flushed with nitrogen and the contents are removedand filtered through filter aid to remove catalyst. After removal of thesolvent 74 g of crude material was obtained. The intermediated is useddirectly in the next step without purification. MS (m/e): 158.3 (M+H⁺)

Step 2

A solution of the trans-(4-amino-cyclohexyl)-acetic acid obtained (74 g,476 mmol) is adjusted to pH 5 with 25% HCl. The mixture was evaporatedto dryness and dried under vacuum overnight. The residue was suspendedin 146 mL of a 6.5N ethanolic HCl solution and 0.6 L of ethanol wereadded to the mixture. After 4 h refluxing, the mixture is cooled andfiltered and the filtrate is concentrated to dryness under vacuum. Theresidue is dissolved in ethanol, treated with ether and cooled overnightin the refrigerator to give the trans-(4-Amino-cyclohexyl)-acetic acidethyl ester hydrochloride (19.7 g, 32% on the two steps) as a whitesolid which was filtered and dried under vacuum. MS (m/e): 186.1 (M+H⁺)

Intermediate C Step 1Trans-(4-tert-Butoxycarbonylamino-cyclohexyl)-acetic acid ethyl ester

To a solution of trans-(4-Amino-cyclohexyl)-acetic acid ethyl ester(1.28 g, 7 mmol), in dichloromethane (15 mL), di-tert-butyl-dicarbonate(2.26 g, 10 mmol), triethylamine (0.699 mL, 7 mmol) and4-dimethylaminopyridine (0.042 mL, 0.35 mmol) were added. The mixturewas stirred for 8 h until TLC indicated completion of the reaction.Water was added and the solution was extracted three times withdichloromethane. The combined organic layers were washed with water andbrine, dried over magnesium sulfate, filtered and evaporated. The crudeproduct was purified by flash-chromatography on silica gel withhexane:ethyl acetate (4:2 to 3:2) to give 1.2 g (60%) of the product asa white solid. MS (m/e): 284.4 (M−H⁺).

Step 2 Trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester

To a solution of trans-(4-tert-Butoxycarbonylamino-cyclohexyl)-aceticacid ethyl ester (1.04 g, 4 mmol), in toluene (10 mL) at −78° C. a 1.2Msolution of DIBAL-H (5.1 mL, 6 mmol) in toluene was added. The mixturewas stirred at −78° C. until TLC after 0.5 h indicated completion of thereaction. Water was added and the solution was extracted three timeswith dichloromethane. The combined organic layers were washed with waterand brine, dried over magnesium sulfate, filtered and evaporated. Thecrude product was used without purification on the next step. MS (m/e):242.3 (M+H⁺).

Intermediate E Trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamicacid tert-butyl ester

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4 g, 18.1mmol), trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester(5.4 g, 22.7 mmol), in 1, 2 dichloroethane (55 mL) was stirred for 4 hat room temperature and sodium triacetoxyborohydride (6.9 g, 32.7 mmol)was added slowly and the resulting solution was stirred for 12 hoursuntil the TLC indicated completion of the reaction. The mixture wasfiltrated and concentrated to dryness and purified with columnchromatography on silica gel using CH₂Cl₂-CH₂Cl₂/MeOH (1-9:1). Theproduct fractions were concentrated to give 9.4 g (21 mmol, 100% yield)of a light brown solid. MS (m/e): 446.3 (M+H⁺).

Intermediate F Trans4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(could be obtained as the trifluoroacetic acid salt)

9.4 g (21 mmol) of(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamicacid tert-butyl ester is solved in dichloromethane (100 mL) andtrifluoroacetic acid is added at 0° C. (13.3 mL, 174 mmol) and themixture is stirred at room temperature overnight. NaHCO₃ is slowly addeduntil pH 9 and the mixture extracted 3 times with dichloromethane andethyl acetate. The solvent was evaporated to yield 5.5 g (16 mmol, 77%)of a light brown solid that was used without purification on the nextsteps. MS (m/e): 346.5 (M+H⁺).

4N-trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide

4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(0.03 g, 0.087 mmol) is suspended in dichloromethane (0.600 mL) andtriethylamine is added (0.013 mL, 0.096 mmol) followed by acetylchloride(0.008 mL, 0.104 mmol) and the mixture was stirred for 30 minutes atroom temperature until TLC indicated the end of the reaction. Sodiumbicarbonate solution was added until pH 9 and the reaction extracted 3times with dichloromethane. The organic phase was dried and purifiedwith column chromatography on silica gel using CH₂Cl₂-CH₂Cl₂/MeOH(1-9:1). The product fractions were concentrated to give 0.022 g (0.056mmol, 65% yield) of a white solid. MS (m/e): 388.5 (M+H⁺).

Example 2 Tetrahydro-pyran-4-carboxylic acid trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide

Tetrahydro-pyran-4-carboxylic acid (0.013 g, 0.096 mmol),2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate(0.026 g, 0.08 mmol) and (0.04 mL, 0.24 mmol) of N-ethyldiisopropylaminewere stirred in 0.6 mL of DMF for 0.5 h at room temperature and Trans4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(could be obtained as the trifluoroacetic acid salt) (trifluoro aceticacid salt) (0.030 g, 0.08 mmol) was added. The mixture was stirred for12 hours at room temperature. The mixture was concentrated to drynessand the residue was taken up on methanol and purified with preparativeHPLC on reversed phase eluting with acetonitrile/water. The combinedproducted fractions were evaporated under reduced pressure to yield0.027 g of a off-white solid (0.06 mmol, 74%). MS (m/e): 458.5 (M+H⁺).

According to the procedure described for the synthesis of example 2further derivatives have been synthesized from the respective Trans4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(could be obtained as the trifluoroacetic acid salt) and thecorresponding acid. They comprise examples 2 to 41 on Table 1.

TABLE 1 MW found Ex. Systematic name MW Starting materials (M + H)⁺  2Tetrahydro-pyran-4- 457.59 Trans 4-{2-[4-(6-Fluoro- 458.5 carboxylicacid trans (4- benzo[d]isoxazol-3-yl)- {2-[4-(6-fluoro-piperidin-1-yl]-ethyl}- benzo[d]isoxazol-3-yl)- cyclohexylamine (couldbe piperidin-1-yl]-ethyl}- obtained as the trifluoroaceticcyclohexyl)-amide acid salt) and Tetrahydro- pyran-4-carboxylic acid  3N-trans (4-{2-[4-(6- 431.55 Trans 4-{2-[4-(6-Fluoro- 432.2Fluoro-benzo[d]isoxazol- benzo[d]isoxazol-3-yl)- 3-yl)-piperidin-1-yl]-piperidin-1-yl]-ethyl}- ethyl}-cyclohexyl)-3- cyclohexylamine (could bemethoxy-propionamide obtained as the trifluoroacetic acid salt) and3-methoxy- propionic acid  4 N-trans-(4-{2-[4-(6- 534.68 Trans4-{2-[4-(6-Fluoro- 535.5 Fluoro-benzo[d]isoxazol-benzo[d]isoxazol-3-yl)- 3-yl)-piperidin-1-yl]- piperidin-1-yl]-ethyl}-ethyl}-cyclohexyl)-4- cyclohexylamine (could be morpholin-4-yl- obtainedas the trifluoroacetic benzamide acid salt) and 4-morpholin-4-yl-benzoic acid  4A N-Trans (4-{2-[4-(6- 535.6 Trans 4-{2-[4-(6-Fluoro-536.0 Fluoro-benzo[d]isoxazol- benzo[d]isoxazol-3-yl)-3-yl)-piperidin-1-yl]- piperidin-1-yl]-ethyl}- ethyl}-cyclohexyl)-6-cyclohexylamine (could be morpholin-4-yl- obtained as thetrifluoroacetic nicotinamide acid salt) and 6-morpholino nicotinic acid 4B 5-Morpholin-4-yl- 536.6 Trans 4-{2-[4-(6-Fluoro- 537.2pyrazine-2-carboxylic benzo[d]isoxazol-3-yl)- acid trans (4-{2-[4-(6-piperidin-1-yl]-ethyl}- fluoro-benzo[d]isoxazol- cyclohexylamine (couldbe 3-yl)-piperidin-1-yl]- obtained as the trifluoroaceticethyl}-cyclohexyl)-amide acid salt) and 5-Morpholin-4-yl-pyrazine-2-carboxylic acid (ester prepared by substitution of Chloroderivative using Morpholine with TEA in Dioxane at 45° C. during 16hours)  4C 6-Morpholin-4-yl- 536.6 Trans 4-{2-[4-(6-Fluoro- 537.5pyridazine-3-carboxylic benzo[d]isoxazol-3-yl)- acid-trans (4-{2-[4-(6-piperidin-1-yl]-ethyl}- fluoro-benzo[d]isoxazol- cyclohexylamine (couldbe 3-yl)-piperidin-1-yl]- obtained as the trifluoroaceticethyl}-cyclohexyl)-amide acid salt) and 6-Morpholin-4-yl-pyridazine-3-carboxylic acid (ester prepared by substitution ofChloro derivative using Morpholine with TEA in Dioxane at 45° C. during16 hours  4D 2-Morpholin-4-yl- 536.6 Trans 4-{2-[4-(6-Fluoro- 537.7pyrimidine-5-carboxylic benzo[d]isoxazol-3-yl)- acid trans (4-{2-[4-(6-piperidin-1-yl]-ethyl}- fluoro-benzo[d]isoxazol- cyclohexylamine (couldbe 3-yl)-piperidin-1-yl]- obtained as the trifluoroaceticethyl}-cyclohexyl)-amide acid salt) and 2-morpholin-4-yl-pyrimidine-5-carboxylic acid (commercial available)  53-Fluoro-N-trans (4-{2- 552.6 Trans 4-{2-[4-(6-Fluoro- 553.5[4-(6-fluoro- benzo[d]isoxazol-3-yl)- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- piperidin-1-yl]-ethyl}- cyclohexylamine (couldbe cyclohexyl)-4- obtained as the trifluoroacetic morpholin-4-yl- acidsalt) and 3-Fluoro-4- benzamide morpholin-4-yl-benzoic acid (prepared byLiOH hydrolysis of the methyl ester commercial available)  64-Dimethylamino-N- 492.6 Trans 4-{2-[4-(6-Fluoro- 493.1 trans(4-{2-[4-(6-fluoro- benzo[d]isoxazol-3-yl)- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- piperidin-1-yl]-ethyl}- cyclohexylamine (couldbe cyclohexyl)-benzamide obtained as the trifluoroacetic acid salt) and4- Dimethylamino benzoic acid  7 2-Benzo[1,3]dioxol-5-yl- 507.6 Trans4-{2-[4-(6-Fluoro- 508.4 N-trans (4-{2-[4-(6- benzo[d]isoxazol-3-yl)-fluoro-benzo[d]isoxazol- piperidin-1-yl]-ethyl}- 3-yl)-piperidin-1-yl]-cyclohexylamine (could be ethyl}-cyclohexyl)- obtained as thetrifluoroacetic acetamide acid salt) and 3,4- (methylenedioxy)phenylacetic acid  8 N-trans-(4-{2-[4-(6- 479.6 Trans 4-{2-[4-(6-Fluoro-480.3 Fluoro-benzo[d]isoxazol- benzo[d]isoxazol-3-yl)-3-yl)-piperidin-1-yl]- piperidin-1-yl]-ethyl}- ethyl}-cyclohexyl)-4-cyclohexylamine (could be methoxy-benzamide obtained as thetrifluoroacetic acid salt) and 4-methoxy- benzoic acid  94-tert-Butoxy-N-trans (4- 521.7 Trans 4-{2-[4-(6-Fluoro- 522.7{2-[4-(6-fluoro- benzo[d]isoxazol-3-yl)- benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}- piperidin-1-yl]-ethyl}- cyclohexylamine (couldbe cyclohexyl)-benzamide obtained as the trifluoroacetic acid salt) and4-tert-Butoxy- benzoic acid 10 4-Chloro-N-trans (4-{2- 484.01 Trans4-{2-[4-(6-Fluoro- 484.4 [4-(6-fluoro- benzo[d]isoxazol-3-yl)-benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}- piperidin-1-yl]-ethyl}-cyclohexylamine (could be cyclohexyl)-benzamide obtained as thetrifluoroacetic acid salt) and 4-tert-chloro- benzoic acid 114-(1,1-Dioxo-1,6- 582.74 Trans 4-{2-[4-(6-Fluoro- 583.2thiomorpholin-4-yl)-N- benzo[d]isoxazol-3-yl)- trans (4-{2-[4-(6-fluoro-piperidin-1-yl]-ethyl}- benzo[d]isoxazol-3-yl)- cyclohexylamine (couldbe piperidin-1-yl]-ethyl}- obtained as the trifluoroaceticcyclohexyl)-benzamide acid salt) and 4-(1,1-Dioxo-1,6-thiomorpholin-4-yl)-benzoic acid 12 N-trans (4-{2-[4-(6- 535.66 Trans4-{2-[4-(6-Fluoro- 536.5 Fluoro-benzo[d]isoxazol-benzo[d]isoxazol-3-yl)- 3-yl)-piperidin-1-yl]- piperidin-1-yl]-ethyl}-ethyl}-cyclohexyl)-2- cyclohexylamine (could be morpholin-4-yl- obtainedas the trifluoroacetic isonicotinamide acid salt) and 2-morpholin-4-yl-isonicotinic acid 13 N-trans (4-{2-[4-(6- 480.6 Trans4-{2-[4-(6-Fluoro- 481.4 Fluoro-benzo[d]isoxazol-benzo[d]isoxazol-3-yl)- 3-yl)-piperidin-1-yl]- piperidin-1-yl]-ethyl}-ethyl}-cyclohexyl)-2- cyclohexylamine (could be methoxy-isonicotinamideobtained as the trifluoroacetic acid salt) and 2-methoxy- isonicoticacid 14 N-trans (4-{2-[4-(6- 532.7 Trans 4-{2-[4-(6-Fluoro- 533.3Fluoro-benzo[d]isoxazol- benzo[d]isoxazol-3-yl)- 3-yl)-piperidin-1-yl]-piperidin-1-yl]-ethyl}- ethyl}-cyclohexyl)-4- cyclohexylamine (could bepiperidin-1-yl-benzamide obtained as the trifluoroacetic acid salt) and4-piperidin-1-yl- benzoic acid 15 2,3-Dihydro- 507.6 Trans4-{2-[4-(6-Fluoro- 508.4 benzo[1,4]dioxine-2- benzo[d]isoxazol-3-yl)-carboxylic acid trans (4- piperidin-1-yl]-ethyl}- {2-[4-(6-fluoro-cyclohexylamine (could be benzo[d]isoxazol-3-yl)- obtained as thetrifluoroacetic piperidin-1-yl]-ethyl}- acid salt) and 2,3-Dihydro-cyclohexyl)-amide benzo[1,4]dioxine-2-carboxylic acid 16 N-trans(4-{2-[4-(6- 467.6 Trans 4-{2-[4-(6-Fluoro- 468.4Fluoro-benzo[d]isoxazol- benzo[d]isoxazol-3-yl)- 3-yl)-piperidin-1-yl]-piperidin-1-yl]-ethyl}- ethyl}-cyclohexyl)-2-(3- cyclohexylamine (couldbe methyl-pyrazol-1-yl)- obtained as the trifluoroacetic acetamide acidsalt) and (3-Methyl- pyrazol-1-yl)-acetic acid 17 N-trans(4-{2-[4-(6-514.6 Trans 4-{2-[4-(6-Fluoro- 515.0 Fluoro-benzo[d]isoxazol-benzo[d]isoxazol-3-yl)- 3-yl)-piperidin-1-yl]- piperidin-1-yl]-ethyl}-ethyl}-cyclohexyl)-4- cyclohexylamine (could be pyrrol-1-yl-benzamideobtained as the trifluoroacetic acid salt) and 4-pyrrol-1-yl- benzoicacid 18 1-Hydroxy- 429.5 Trans 4-{2-[4-(6-Fluoro- 430.3cyclopropanecarboxylic benzo[d]isoxazol-3-yl)- acid trans (4-{2-[4-(6-piperidin-1-yl]-ethyl}- fluoro-benzo[d]isoxazol- cyclohexylamine (couldbe 3-yl)-piperidin-1-yl]- obtained as the trifluoroaceticethyl}-cyclohexyl)-amide acid salt) and 1-Hydroxy-cyclopropanecarboxylic acid 19 1-Trifluoromethyl- 495.6 Trans4-{2-[4-(6-Fluoro- 496.1 cyclobutanecarboxylic benzo[d]isoxazol-3-yl)-acid trans (4-{2-[4-(6- piperidin-1-yl]-ethyl}- fluoro-benzo[d]isoxazol-cyclohexylamine (could be 3-yl)-piperidin-1-yl]- obtained as thetrifluoroacetic ethyl}-cyclohexyl)-amide acid salt) and 1-Trifluoromethyl- cyclobutanecarboxylic acid 20 3,3,3-Trifluoro-N-trans455.5 Trans 4-{2-[4-(6-Fluoro- 456.3 (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)- benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}-piperidin-1-yl]-ethyl}- cyclohexylamine (could be cyclohexyl)- obtainedas the trifluoroacetic propionamide acid salt) and 3,3,3-Trifluoropropionic acid 21 2-(3,5-Dimethoxy- 523.6 Trans 4-{2-[4-(6-Fluoro- 524.3phenyl)-N-trans (4-{2-[4- benzo[d]isoxazol-3-yl)- (6-fluoro-piperidin-1-yl]-ethyl}- benzo[d]isoxazol-3-yl)- cyclohexylamine (couldbe piperidin-1-yl]-ethyl}- obtained as the trifluoroaceticcyclohexyl)-acetamide acid salt) and 2-(3,5- Dimethoxy-phenyl)-aceticacid 22 4-(2,6-Dimethyl- 562.7 Trans 4-{2-[4-(6-Fluoro- 563.5morpholin-4-yl)-N-trans benzo[d]isoxazol-3-yl)- (4-{2-[4-(6-fluoro-piperidin-1-yl]-ethyl}- benzo[d]isoxazol-3-yl)- cyclohexylamine (couldbe piperidin-1-yl]-ethyl}- obtained as the trifluoroaceticcyclohexyl)-benzamide acid salt) and 4-(2,6-Dimethyl-morpholin-4-yl)-benzoic acid 23 Benzo[1,3]dioxole-5- 498.6 Trans4-{2-[4-(6-Fluoro- 499.5 carboxylic acid trans (4-benzo[d]isoxazol-3-yl)- {2-[4-(6-fluoro- piperidin-1-yl]-ethyl}-benzo[d]isoxazol-3-yl)- cyclohexylamine (could bepiperidin-1-yl]-ethyl}- obtained as the trifluoroaceticcyclohexyl)-amide acid salt) and Benzo[1,3]dioxole-5-carboxylic acid

Example 24 N-trans(4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamideIntermediate E Trans(4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamicacid tert-butyl ester

A mixture of 5-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (1.3 g, 5mmol), trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester(example 1, intermediate C) (1.6 g, 6 mmol), triethylamine (0.64 mL, 5mmol) in 1, 2 dichloroethane (27 mL) was stirred for 4 h at roomtemperature and sodium triacetoxyborohydride (1.9 g, 9 mmol) was addedslowly and the resulting solution was stirred for 12 hours until the TLCindicated completion of the reaction. The mixture was filtrated andconcentrated to dryness and purified with column chromatography onsilica gel using CH₂Cl₂-CH₂Cl₂/MeOH (1-9:1). The product fractions wereconcentrated to give 2.3 g (5.1 mmol, 100% yield) of a off-white solid.MS (m/e): 446.3 (M+H⁺).

Intermediate F Trans4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine;compound with trifluoro-acetic acid

2.3 g (5 mmol) of trans(4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamicacid tert-butyl ester is solved in dichloromethane (15 mL) andtrifluoroacetic acid is added at 0° C. (10.7 mL, 46 mmol) and themixture is stirred at room temperature overnight. NaHCO₃ is slowly addeduntil pH 9 and the mixture extracted 3 times with dichloromethane andethyl acetate. The solvent was evaporated to yield 1.86 g (5.3 mmol,100%) of a white solid that was used without purification on the nextsteps. MS (m/e): 346.3 (M+H⁺).

N-trans(4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide

Prepared as described on example 1 from Trans4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylaminein dichloromethane with triethylamine and acetylchloride. MS (m/e):388.3 (M+H⁺).

Example 25 N-trans(4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide

4-morpholinobenzoic acid (0.153 g, 0.74 mmol),2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate(0.026 g, 0.69 mmol) and (0.350 mL, 2.02 mmol) ofN-ethyldiisopropylamine were stirred in 5 mL of DMF for 0.5 h at roomtemperature and Trans4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(trifluoro acetic acid salt) (0.300 g, 0.69 mmol) was added. The mixturewas stirred for 12 hours at room temperature. The mixture wasconcentrated to dryness and the residue was taken up on methanol andpurified with chromatography eluting with CH₂Cl₂-CH₂Cl₂/MeOH (1-9:1).The combined producted fractions were evaporated under reduced pressureto yield 0.24 g of an off-white solid (0.5 mmol, 70%). MS (m/e): 535.3(M+H⁺).

Example 26 N-trans(4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide

Prepared as described on example 25 using 3-methoxy-propionic acid and),2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate,N-ethyldiisopropylamine in DMF and Trans4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(trifluoroacetic acid salt) to yield 0.023 g of a white solid (0.05mmol, 37%). MS (m/e): 332.4 (M+H⁺).

Example 27 N-trans(4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-piperidin-1-yl-benzamide

Prepared as described on example 26 using 4-piperidin-1-yl-benzoic acid,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate,N-ethyldiisopropylamine in DMF and Trans4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(trifluoroacetic acid salt). The mixture was stirred for 12 hours atroom temperature. The mixture was concentrated to dryness and theresidue was taken up on methanol and purified with preparative HPLC onreversed phase eluting with acetonitrile/water.

The combined producted fractions were evaporated under reduced pressureto yield 0.028 g of a off-white solid (0.05 mmol, 49%). MS (m/e): 533.0(M+H⁺).

According to the procedure described for the synthesis of example 26further derivatives have been synthesized from the respective Trans4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(trifluoroacetic acid salt) and the corresponding acid. They compriseexamples 28 to 30 on Table 2.

TABLE 2 MW found (M + Ex. Systematic name MW Starting materials H)⁺ 284-(2,6-Dimethyl-morpholin- 562.7 Trans 4-{2-[4-(5-Fluoro- 563.04-yl)-N-trans (4-{2-[4-(5- benzo[d]isoxazol-3-yl)-fluoro-benzo[d]isoxazol-3- piperidin-1-yl]-ethyl}-yl)-piperidin-1-yl]-ethyl}- cyclohexylamine cyclohexyl)-benzamide(trifluoroacetic acid salt) and 4-morpholinobenzoic acid 294-(1,1-Dioxo-1,6,4- 582.7 Trans 4-{2-[4-(5-Fluoro- 583.2thiomorpholin-4-yl)-N benzo[d]isoxazol-3-yl)- trans-(4-{2-[4-(5-fluoro-piperidin-1-yl]-ethyl}- benzo[d]isoxazol-3-yl)- cyclohexylaminepiperidin-1-yl]-ethyl}- (trifluoroacetic acid salt)cyclohexyl)-benzamide and 4-(1,1-Dioxo thiomorpholino) benzoic acid 30Benzo[1,3]dioxole-5- 493.5 Trans 4-{2-[4-(5-Fluoro- 494.4 carboxylicacid trans (4- benzo[d]isoxazol-3-yl)- {2-[4-(5-fluoro-piperidin-1-yl]-ethyl}- benzo[d]isoxazol-3-yl)- cyclohexylaminepiperidin-1-yl]-ethyl}- (trifluoroacetic acid salt) cyclohexyl)-amideand Benzo[1,3]dioxole- 5-carboxylic acid

Example 32 N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamideIntermediate D 1-[4-(2,4-Dichloro-benzoyl)-piperidin-1-yl]-ethanone

Aluminium chloride (11, 24 g, 84 mmol) is added portionwise to 23 mL ofdichlorobenzene (200 mmol). To this suspension 8 g of1-acetylisonipecotoyl chloride (42 mmol) was added also portionwise. Themixture was stirred 10 minutes at room temperature and then at 90° C.for 4 hours until TLC indicated completion of the reaction that changedfrom a yellow/orange solution changed into dark orange upon heating.Water was added and the solution was extracted three times withdichloromethane. The combined organic layers were washed with water andbrine, dried over magnesium sulfate, filtered and evaporated. The crudeproduct was purified by flash-chromatography on silica gel withhexane:ethyl acetate (1:0 to 0:1) to give 6.3 g (50%) of the product asan orange oil. MS (m/e): 300.2 (M⁺).

1-(4-{(2,4-Dichloro-phenyl)-[(E)-hydroxyimino]-methyl}-piperidin-1-yl)-ethanone

1-[4-(2,4-Dichloro-benzoyl)-piperidin-1-yl]-ethanone (5.6 g, 19 mmol)was solved in ethanol (140 mL). Hydroxylamine (5.2 g, 75 mmol) was addedfollowed by N,N-diisopropyl ethyl amine (12.8 mL, 75 mmol) and thereaction was refluxed to 100° C. for 12-20 hours until TLC indicatedcompletion of the reaction. Water was added and the solution wasextracted three times with dichloromethane. The combined organic layerswere washed with water and brine, dried over magnesium sulfate, filteredand evaporated. The crude product was purified by flash-chromatographyon silica gel with hexane:ethyl acetate (1:0 to 0:1) to give 2.15 g(37%) of the product as a white solid and 1.12 g of the startingmaterial that was recovered. MS (m/e): 315.1 (M+H⁺).

1-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethanone

1-(4-{(2,4-Dichloro-phenyl)-[(E)-hydroxyimino]-methyl}-piperidin-1-yl)-ethanone(2.15 g, 7 mmol) was solved in THF (34 mL) and potassium tert-butoxidewas added (0.844 g, 7.5 mmol). The mixture was stirred for 2 hours untilTLC indicated the end of the reaction. The solvent was removed and themixture purified by flash-cromatography on silica gel with hexane:ethylacetate (1:0 to 0:1). The combined producted fractions were evaporatedunder reduced pressure to yield 1.45 g of a colourless oil (75%). MS(m/e): 279.1 (M+H⁺).

6-Chloro-3-piperidin-4-yl-benzo[d]isoxazole hydrochloride

1-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethanone (1.45 g,5.3 mmol) was diluted with an aqueous solution of HCl 6N (13.8 mL, 16mmol) and the mixture was refluxed overnight. After cooling, 2×20 mL ofether was added and the mixture extracted. A solution of NaOH was addedto the aqueous phase until pH 11 and the mixture was extracted withethyl acetate three times. The combined ethyl acetate fractions weredried and evaporated under reduced pressure to yield 1.14 g of a lightbrown solid (93%). MS (m/e): 236.9 (M+H⁺).

Intermediate E Trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamicacid tert-butyl ester

Prepared as described for intermediate F (example 1) from a mixture6-Chloro-3-piperidin-4-yl-benzo[d]isoxazole hydrochloride (0.942 g, 4mmol), trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester(1.06 g, 4 mmol) and sodium triacetoxyborohydride (1.51 g, 7 mmol) in 1,2 dichloroethane (9.8 mL) The product fractions were concentrated togive 1.2 g (2.6 mmol, 64.3% yield) of a light brown solid. MS (m/e):462.4 (M+H⁺).

Intermediate F Trans4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(could be obtained as the trifluoroacetic acid salt)

Prepared as described for example 1 from Trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamicacid tert-butyl ester and trifluoroacetic acid at 0° C. The product wasobtained as a light yellow solid (0.197 g, 52%). MS (m/e): 362.4 (M+H⁺).

N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide

Prepared as described for example 2 from 3-methoxy-propionic acid,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate,N-ethyldiisopropylamine and Trans4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(trifluoro acetic acid salt) in DMF for 12 hours at room temperature.The mixture was concentrated to dryness and the residue was taken up onmethanol and purified with chromatography eluting withCH₂Cl₂-CH₂Cl₂/MeOH (1-9:1). The combined producted fractions wereevaporated under reduced pressure to yield 0.022 g of an off-white solid(0.05 mmol, 45%). MS (m/e): 448.3 (M+H⁺).

According to the procedure described for the synthesis of example 32further derivatives have been synthesized from Trans4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamineand the corresponding acids: commercially available, or obtained bymethods known on the art (e.g. hydrolysis of the corresponding ester) orby methods described hereinbefore (see Table 3).

TABLE 3 MW Ex. found No Systematic name MW Starting materials (M + H)+33 N-trans-(4-{2-[4-(6-Chloro- 487.9 Trans 4-{2-[4-(6-Chloro- 488.1benzo[d]isoxazol-3-yl)- benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}-piperidin-1-yl]-ethyl}- cyclohexyl)-3,3,3-trifluoro-2- cyclohexylamine(trifluoro- hydroxy-propionamide acetic acid salt) and 3,3,3-trifluoro-2-hydroxy-propionic acid (commercially available) 34 N-trans(4-{2-[4-(6-Chloro- 488.0 Trans 4-{2-[4-(6-Chloro- 488.3 34Abenzo[d]isoxazol-3-yl)- benzo[d]isoxazol-3-yl)- 34Bpiperidin-1-yl]-ethyl}- piperidin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro- cyclohexylamine (trifluoro-pyran-2-yl)-acetamide acetic acid salt) and 2-(tetrahydro-pyran-2-yl)-acetic acid (commercially available) Note:Chiral separation yields both enantiomers. 34A N-trans(4-{2-[4-(6-Chloro- 488.0 Separation of racemic mixture 488.4benzo[d]isoxazol-3-yl)- by chiral column piperidin-1-yl]-ethyl}-cyclohexyl)-2-(R)- tetrahydro-pyran-2-yl- acetamide 34B N-trans(4-{2-[4-(6-Chloro- 488.0 Separation of racemic mixture 488.4benzo[d]isoxazol-3-yl)- by chiral column piperidin-1-yl]-ethyl}-cyclohexyl)-2-(S)- tetrahydro-pyran-2-yl- acetamide 35N-trans-(4-{2-[4-(6-Chloro- 516.12 Trans 4-{2-[4-(6-Chloro- 516.5benzo[d]isoxazol-3-yl)- benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}-piperidin-1-yl]-ethyl}- cyclohexyl)-2-trans (4- cyclohexylamine(trifluoro- methoxy-cyclohexyl)- acetic acid salt) and Trans (4-acetamide Methoxy-cyclohexyl)-acetic acid (prepared from Methyl 4-hydroxyphenyl acetate and Nickel-aluminum alloy in MeOH and posteriormethylation with NaH, MeI and ester hydrolysis with LiOH) 36 N-trans(4-{2-[4-(6-Chloro- 544.1 Trans 4-{2-[4-(6-Chloro- 544.0benzo[d]isoxazol-3-yl)- benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}-piperidin-1-yl]-ethyl}- cyclohexyl)-2-(1,4-dioxa- cyclohexylamine(trifluoro- spiro[4.5]dec-8-yl)- acetic acid salt) and (1,4- acetamideDioxa-spiro[4.5]dec-8-yl)- acetic acid (prepared by hydrolysis of theethyl ester commercially available) 37 N-trans-(4-{2-[4-(6-Chloro- 478.0Trans 4-{2-[4-(6-Chloro- 478.1 benzo[d]isoxazol-3-yl)-benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}- piperidin-1-yl]-ethyl}-cyclohexyl)-3,3-dimethoxy- cyclohexylamine (trifluoro- propionamideacetic acid salt) and 3,3- dimethoxy-propionic acid (prepared byhydrolysis of the commercially available methyl ester) 38N-trans-(4-{2-[4-(6-Chloro- 474.0 Trans 4-{2-[4-(6-Chloro- 474.1benzo[d]isoxazol-3-yl)- benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}-piperidin-1-yl]-ethyl}- cyclohexyl)-2-(tetrahydro- cyclohexylamine(trifluoro- furan-2-yl)-acetamide acetic acid salt) and 2-(tetrahydro-furan-2-yl)-acetic acid (prepared by hydrolysis of thecommercial available methyl ester) 39 (R)-N-trans (4-{2-[4-(6- 448.0Trans 4-{2-[4-(6-Chloro- 448.1 Chloro-benzo[d]isoxazol-3-benzo[d]isoxazol-3-yl)- yl)-piperidin-1-yl]-ethyl}-piperidin-1-yl]-ethyl}- cyclohexyl)-3-hydroxy- cyclohexylamine(trifluoro- butyramide acetic acid salt) and (R)-3- hydroxy-butyric acid40 N-trans (4-{2-[4-(6-Chloro- 504.0 Trans 4-{2-[4-(6-Chloro- 504.0benzo[d]isoxazol-3-yl)- benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}-piperidin-1-yl]-ethyl}- cyclohexyl)-2-((S)-2,2- cyclohexylamine(trifluoro- dimethyl-[1,3]dioxolan-4- acetic acid salt) and-(4S)-2,2-yl)-acetamide dimethyl-[1,3]dioxolan-4-yl)- acetic acid potassium salt(prepared by KO^(t)SiMe₃ conversion of methyl ester to the anhydrousacid salt following Tet. Letters, 25(51), 1984, 5831-5834) 41 N-trans(4-{2-[4-(6-Chloro- 502.1 Trans 4-{2-[4-(6-Chloro- 502.1benzo[d]isoxazol-3-yl)- benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}-piperidin-1-yl]-ethyl}- cyclohexyl)-2-((1S,3S)-3- cyclohexylamine(trifluoro- methoxy-cyclopentyl)- acetic acid salt) and ((1S,3S)-3-acetamide Methoxy-cyclopentyl)-acetic acid potassium salt (prepared byKO^(t)SiMe₃ conversion of methyl ester to the anhydrous acid of thecorresponding methyl ester synthesized following Helvetica Chimica Acta,Vol 75, 1992, 1945-1950)

Example 42 N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-4-methyl-cyclohexyl)-acetamide8-Methyl-1,4-dioxa-spiro (4,5) decan-8-ol

Prepared by treatment of 1,4,-cyclohexanedione monoethylene acetal withmethyl lithium in ether or MeMg I according to the procedure describedon Journal of Organic Chemistry, 71(22), 2006, 8424-8430.

4-Methoxy-4-methyl-cyclohexanone

Prepared from reaction of 8-Methyl-1,4-dioxa-spiro(4,5) decan-8-ol (11.7g, 68 mmol), NaH (137 mmol), MeI (273 mmol) and Me₄NBr (17 mmol) intetrahydrofuran (150 mL) at room temperature to obtain the o-methylated1,4-dioxa spiro compound followed by treatment with 25% HCl (13.5 mL) inacetone to obtain (9.48 g, 97.6%) of the desired4-Methoxy-4-methyl-cyclohexanone as an oil.

(4-Methoxy-4 methyl-cyclohexylidene)-acetic acid methyl ester

A mixture of trimethyl phosphonoacetate (9.11 mL, 56 mmol) and (40 mL,64 mmol) of n-BuLi (1.6N) in DME (60 mL) is stirred for 10 minutes at 0°C. 4-Hydroxy-4-methyl-cyclohexanone (8 g, 56 mmol) was added and themixture stirred 2.5 hours at 0° C. until TCL indicated complexion of thereaction. Product was obtained after extraction with dichloromethane(7.71 g, 69%).

(4-cis/trans-Methoxy-4-methyl-cyclohexyl)acetic acid methyl ester

Prepared from (4-Methoxy-4 methyl-cyclohexexylidene)-acetic acid methylester (7 g, 35 mmol) with Pd/C (10%) (35 mmol) in ethyl acetate underhydrogen overnight at room temperature. MS (m/e): 201.2 (M+H⁺).

N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-cis,trans-methoxy-4-methyl-cyclohexyl)-acetamide

(4-cis/trans-Methoxy-4-methyl-cyclohexyl)acetic acid (anhydrouspotassium salt) was prepared by conversion of(4-cis/trans-Methoxy-4-methyl-cyclohexyl)acetic acid methyl ester (0.157g, 1 mmol) to the anhydrous acid salt using potassiumtrimethylsilanolate KO^(t)SiMe₃ (0.202 g, 2 mmol) and stirring with 2 mLof dichloromethane overnight following Tet. Letters, 25(51), 1984,5831-5834. The solvent was evaporated and the obtained salt was solvedon DMF (2 mL) and reacted as described for example 32, with Trans4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(trifluoro acetic acid salt) (0.300 g, 1 mol)2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate(0.328 g, 1 mmol) and (0.530 mL, 3 mmol) of N-ethyldiisopropylamine for12 hours at room temperature. MS (m/e): 530.0 (M+H⁺).

Example 42A N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-trans-methoxy-4-methyl-cyclohexyl)-acetamide

Obtained from separation using a chiral column (chiralpak AD) of the cisand trans mixture of N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-4-methyl-cyclohexyl)-acetamide.MS (m/e): 530.0 (M+H⁺).

Example 42B N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-cis-methoxy-4-methyl-cyclohexyl)-acetamide

Obtained from separation using a chiral column (chiralpak AD) of the cisand trans mixture of N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-cis-methoxy-4-methyl-cyclohexyl)-acetamide.MS (m/e): 530.1 (M+H⁺).

Example 43 N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide

Prepared as described for example 32 from 3-methoxy-butyric acid andTrans4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(trifluoro acetic acid salt) in DMF for 4-12 hours at room temperature.MS (m/e): 462.3 (M+H⁺).

Example 43A (R)—N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide

Obtained from separation using a chiral column (chiralpak AD) of N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide.MS (m/e): 462.5 (M+H⁺).

Example 43B(S)—N-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide

Obtained from separation using a chiral column (chiralpak AD) of N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide.MS (m/e): 462.5 (M+H⁺).

Example 44N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-trans(4-methoxymethyl-cyclohexyl)-acetamide8-Methoxymethyl-1,4-dioxa-spiro[4.5]decane

1,4-Dioxaspiro[4.5]decane-8-methanol (2 g, 1 mmol) (commercial availableor prepared as in Bioorganic & Medicinal Chemistry, 13(23), 6309-6323;2005) is methylated using MeI (1.81 mL, 29 mmol) and NaH (0.813 g, 20mmol) in tetrahydrofuran to obtain after 2 hours of stirring at roomtemperature 1.4 g (7.8 mmol) of the desired compound. MS (m/e): 187.3(M+H⁺).

(4-Methoxymethyl-cyclohexylidene)-acetic acid methyl ester

4-Methoxymethyl-cyclohexanone was obtained by treatment of8-Methoxymethyl-1,4-dioxa-spiro[4.5]decane (1.45 g, 8 mmol) with HCl 1N(15.6 mL, 16 mmol) in acetone (35 mL). Acetone was removed and theproduct was extracted with dichloromethane. The crude4-Methoxymethyl-cyclohexanone was solved in 1 mL of dimethoxyethane andadded into a mixture previously prepared by adding n-BuLi (3.54 mL, 6mmol) to methyl diethylphosphonoacetate ((1.03 g, 5 mmol) in DME bystirring for 10 minutes at 0° C. After 2 hours TLC indicated formationof the (4-Methoxymethyl-cyclohexylidene)-acetic acid methyl ester (0.552g, 2.7 mmol). MS (m/e): 199.1 (M+H⁺).

(4-Methoxymethyl-cyclohexyl)-acetic acid methyl ester

Prepared from (4-Methoxymethyl-cyclohexylidene)-acetic acid methyl ester(0.550 g, 3 mol) by hydrogenation using Pd/C (10%) (0.295 g, 0.3 mmol)in ethylacetate (15 mL).1/3 cis/trans mixture.

N-trans (4-{2-[4-(6Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-trans(4-methoxymethyl-cyclohexyl)-acetamide

Prepared from KO^(t)SiMe₃ and (4-Methoxymethyl-cyclohexyl)-acetic acidmethyl ester to its potassium salt as described on example 42 andreaction of the salt with Trans4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(trifluoro acetic acid salt),2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborateand N-ethyldiisopropylamine for 12 hours at room temperature. Additionof ether and filtration yields the major trans isomer as a white solid.MS (m/e): 530.2 (M+H⁺).

Example 45 N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-hydroxy-4-methyl-cyclohexyl)-acetamide(4-Oxo-cyclohexyl)-acetic acid

Prepared from LiOH hydrolysis of (4-Oxo-Cyclohexyl)-acetic acid methylester (commercially available).

(4-Hydroxy-4-methyl-cyclohexyl)-acetic acid

Prepared using an excess of MeMgBr (26 mmol) in THF (20 ml) with(4-Oxo-cyclohexyl)-acetic acid (13 mmol) as described on Journal ofAmerican Society 93 (1), 1971, 121-129.

N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-hydroxy-4-methyl-cyclohexyl)-acetamide

Prepared as described for example 32 from(4-Hydroxy-4-methyl-cyclohexyl)-acetic acid and Trans4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(trifluoro acetic acid salt) in DMF for 4-12 hours at room temperature.MS (m/e): 516.1 (M+H⁺).

Example 46 N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide

Prepared as described on example 1 from Trans4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(trifluoro acetic acid salt) in dichloromethane with triethylamine andacetylchloride. MS (m/e): 404.4 (M+H⁺).

Example 47 Ethanesulfonic acid (4-trans{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide

Trans4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(could be obtained as the trifluoroacetic acid salt) (intermediate F,example 1) (0.038 g, 0.11 mmol) was solved in THF (0.6 mL),ethanesulfonyl chloride was added followed by triethylamine (0.018 mL,0.13 mmol) and the solution was stirred overnight. The mixture wasconcentrated to dryness and the residue was taken up on methanol andpurified with preparative HPLC on reversed phase eluting withacetonitrile/water. The combined producted fractions were evaporatedunder reduced pressure to yield (0.023 g, 49%) of the product as a whitesolid. MS (m/e):: 438.1 (M+H⁺).

According to the procedure described for the synthesis of example 47further derivatives have been synthesized from the respective Trans4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine (could be obtained as thetrifluoroacetic acid salt) and the corresponding sulfonyl chloride. Theycomprise examples 48 to 50 in table 4 hereinafter.

TABLE 4 MW found Ex. (M + No Systematic name MW Starting materials H)⁺48 4-Chloro-N-trans (4- 520.1 Trans 4-{2-[4-(6-Fluoro- 520.3{2-[4-(6-fluoro- benzo[d]isoxazol-3-yl)- benzo[d]isoxazol-3-piperidin-1-yl]-ethyl}- yl)-piperidin-1-yl]- cyclohexylamine (could beethyl}-cyclohexyl)- obtained as the benzenesulfonamide trifluoroaceticacid chloride salt) and benzenesulfonyl 49 N-trans(4-{2-[4-(6- 515.7Trans 4-{2-[4-(6-Fluoro- 516.3 Fluoro-benzo[d]isoxazol-benzo[d]isoxazol-3-yl)- 3-yl)-piperidin-1-yl]- piperidin-1-yl]-ethyl}-ethyl}-cyclohexyl)-4- cyclohexylamine (could be methoxy- obtained as thebenzenesulfonamide trifluoroacetic acid salt) and 4-methoxy- benzenesulfonyl chloride 50 Pyridine-3-sulfonic acid 487.6 Trans4-{2-[4-(6-Fluoro- 488.2 trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)- benzo[d]isoxazol-3-yl)- piperidin-1-yl]-ethyl}-piperidin-1-yl]-ethyl}- cyclohexylamine (could be cyclohexyl)-amideobtained as the trifluoroacetic acid salt) and pyridine-3- sulfonylchloride hydrochloride

Example 51N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-cyano-acetamide

Prepared in analogy of example 32 from trans4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(trifluoro acetic acid salt) and cyanoacetic acid with triethyl amine asthe base. MS (m/e): 429.4 (M+H⁺).

Example 52N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-cyano-propionamide

Prepared in analogy to example 40 fromtrans-4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(trifluoro-acetic acid salt) and 3-cyanopropionic acid potassium salt(prepared by KO^(t)SiMe₃ conversion of the methyl ester to the anhydrousacid salt following Tett. Letters, 25(51), 1984, 5831-5834). MS (m/e):443.2 (M+H⁺).

Example 53N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl]-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(R)-tetrahydro-furan-2-yl-acetamide

Obtained from separation using a chiral column (chiralpak AD) of N-trans(4-{2-[4-(6Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-furan-2-yl)-acetamide (Example 38). MS (m/e): 474.2 (M+H⁺).

Example 54N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-cyclopropyl-acetamide

The title compound, MS: m/e=444.3 (M+H⁺), was prepared in accordancewith the general method of example 32 from trans4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine (hydrochloric acid salt) andcyclopropylacetic acid.

Example 55N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-hydroxy-acetamide

The title compound, MS: m/e=420.2 (M+H⁺), was prepared in accordancewith the general method of example 32 from trans4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine (hydrochloric acid salt) andglycolic acid.

Example 56N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-methanesulfonyl-acetamide

The title compound, MS: m/e=482.1/484.0 (M+H⁺), was prepared inaccordance with the general method of example 32 from trans4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(hydrochloric acid salt) and methanesulfonylacetic acid.

Example 57N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-[1,3]dioxan-2-yl-acetamideStep 1: [1,3]-Dioxan-2-yl-acetic acid methyl ester

Propane-1,-3-diol (2.45 ml, 36 mmol) was dissolved in 100 ml THF andcooled to 0-5° C. Sodium hydride (1.43 g, 40 mmol, 55%) was added andthe reaction mixture stirred for 15 minutes at 0-5° C. Propyonic acidmethyl ester (2.97 ml, 36 mmol) dissolved in 10 ml THF was added dropwise and stirred for 3 hours at 0-5° C. The reaction mixture wasquenched with 2N HCl-solution and extracted two times with ethylacetate. The organic extracts were washed with brine, dried with sodiumsulfate, filtered and evaporated. The crude product was purified byflash chromatography on silica gel (dichloromethane). The desiredcompound was obtained as a colourless liquid (2.96 g, 52%).

Step 2: N-trans (4-{2-[4-(6Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-[1,3]dioxan-2-yl-acetamide

[1,3]-Dioxan-2-yl-acetic acid methyl ester (130 mg, 0.81 mmol) (Step 1)was dissolved in 2 ml THF, 1 ml methanol and 1 ml water. Lithiumhydroxide monohydrate (102 mg, 2.43 mmol) was added and the reactionmixture stirred for 16 hours at room temperature. The organic solventwas evaporated and the aqueous mixture was acidified with 2N HCl topH 1. The mixture was evaporated to dryness and trans4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine(as a hydrochloric acid salt) (150 mg, 0.41 mmol) (Example 32,Intermediate F) in 1 ml DMF was added. N,N-Diisopropylethylamine (205μl, 1.22 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumtetrafluoroborate [TBTU] (157 mg, 0.49 mmol) were added and the reactionstirred for 2 hours at room temperature. The reaction mixture wasquenched with saturated NaHCO₃-solution and extracted withdichloromethane. The organic extract was washed with brine, dried withsodium sulfate, filtered and evaporated.

The crude product was purified by flash chromatography on silica gel(dichloromethane/methanol 100:0->90:10 gradient). The desired compoundwas obtained as a light yellow solid (61 mg, 33%), MS: m/e=490.3 (M+H⁺).

Example 58N-trans-(4-{2-[4-(5-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-cyclohexyl)-acetamideStep 1: 5-Chloro-3-piperidin-4-yl-benzo[d]isoxazole hydrochloride

The title compound can be prepared in accordance with literaturedescribed in the patent WO02066446 (Example 46 and 48) by using5-chloro-2-fluorobenzaldehyde as starting material.

Step 2: Trans (4-{2-[4-(5Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]ethyl}-cyclohexyl)-carbamicacid tert-butyl ester

The title compound, MS: m/e=462.3 (M+H⁺), was prepared in accordancewith the general method of example 1, intermediate E from a mixture of5-chloro-3-piperidin-4-yl-benzo[d]isoxazole hydrochloride andtrans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester(Example 1, Intermediate C).

Step 3:Trans-4-{2-[4-(5-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylaminehydrochloride

Trans (4-{2-[4-(5Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamicacid tert-butyl ester (1.35 g, 2.92 mmol) was dissolved in 2 mldichloromethane and 4N HCl in dioxane (8.8 ml, 38.8 mmol) was added. Thewhite suspension was stirred for 4 hours at room temperature, dilutedwith diisopropylether and filtered. The crystals were washed withdiisopropylether and dried for 2 hours at 50° C. and <20 mbar, to getthe desired salt as a white solid (1.65 g, quant.) [MS: m/e=362.2(M+H⁺)].

Step 4: N-trans (4-{2-[4-(5Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-cyclohexyl)-acetamide

Prepared as described for Example 40 fromtrans-4-{2-[4-(5-chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylaminehydrochloride (example 58, step 3) andtrans-(4-methoxy-cyclohexyl)-acetic acid potassium salt (prepared frommethyl 4-hydroxyphenyl acetate and Nickel-aluminum alloy in MeOH andposterior methylation with NaH, MeI and by KO^(t)SiMe₃ conversion of themethyl ester to the anhydrous acid salt following Tett. Letters, 25(51),1984, 5831-5834). MS: m/e=516.0/517.1 (M+H⁺).

Example 59N-trans-(4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-methanesulfonamideStep 1:Trans-4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylaminehydrochloride

The title compound, MS: m/e=346.2 (M+H⁺), was prepared in accordancewith the general method of example 58, step 1, 2 and 3 starting from2,5-difluorobenzaldehyde.

Step 2: N-trans (4-{2-[4-(5Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-methanesulfonamide

The title compound, MS: m/e=424.2 (M+H⁺), was prepared in accordancewith the general method of example 47 fromtrans-4{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylaminehydrochloride and methansulfonyl chloride.

Example 60N-trans-(4-{2-[4-(6-Chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamideStep 1:Trans-4-{2-[4-(6-Chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylaminehydrochloride

The title compound, MS: m/e=380.3/382.3 (M+H⁺), was prepared inaccordance with the general method of example 58, step 1, 2 and 3starting from 4-chloro-2,5-difluorobenzaldehyde.

Step 2: N-trans (4-{2-[4-(6Chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide

The title compound, MS: m/e=466.1/468.3 (M+H⁺), was prepared inaccordance with the general method of example 32 fromtrans-4-{2-[4-(6-chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine hydrochloride and3-methoxypropionic acid.

Example 61N-trans-(4-{2-[4-(6-Chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-furan-2-yl)-acetamide

The title compound, MS: m/e=492.3 (M+H⁺), was prepared in accordancewith the general method of example 60 fromtrans-442-[4-(6-chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine hydrochloride and2-(tetrahydro-furan-2-yl)-acetic acid (prepared by hydrolysis of thecommercial available methyl ester).

Example 62N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-methoxy-acetamideStep 1:Trans-4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylaminehydrochloride

The title compound, MS: m/e=364.4 (M+H⁺), was prepared in accordancewith the general method of example 58, step 1, 2 and 3 starting from2,4,5-trifluorobenzaldehyde.

Step 2:N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-methoxy-acetamide

The title compound, MS: m/e=436.3/437.4 (M+H⁺), was prepared inaccordance with the general method of example 32 fromtrans-4-{2-[4-(6-chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylaminehydrochloride and methoxyacetic acid.

Example 63N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-((1R,3R)-3-methoxy-cyclopentyl)-acetamide

The title compound, MS: m/e=504.3 (M+H⁺), was prepared in accordancewith the general method of example 40 fromtrans-4-{2-[4-(5,6-difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylaminehydrochloride (example 62, step 1) andrac-trans-(3-methoxy-cyclopentyl)-acetic acid potassium salt (preparedfrom rac-trans-(3-hydroxy-cyclopentyl)-acetic acid methyl ester(Helvetica Chimica Acta—Vol. 75 (1992) Page 1945 and 1950) and posteriormethylation with NaH, MeI and by KO^(t)SiMe₃ conversion of the methylester to the anhydrous acid salt following Tett. Letters, 25(51), 1984,5831-5834).

Example 64N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-cyclohexyl)-acetamide

The title compound, MS: m/e=518.4 (M+H⁺), was prepared in accordancewith the general method of example 40 fromtrans-4-{2-[4-(5,6-difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine hydrochloride (example 62,step 1) and trans-(4-methoxy-cyclohexyl)-acetic acid potassium salt(prepared from methyl 4-hydroxyphenyl acetate and Nickel-aluminum alloyin MeOH and posterior methylation with NaH, MeI and by KO^(t)SiMe₃conversion of the methyl ester to the anhydrous acid salt followingTett. Letters, 25(51), 1984, 5831-5834).

Example 65N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide

The title compound, MS: m/e=450.3 (M+H⁺), was prepared in accordancewith the general method of example 32 fromtrans-4-{2-[4-(5,6-difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine hydrochloride (example 62,step 1) and 3-methoxypropionic acid.

Example 66N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide

The title compound, MS: m/e=406.3 (M+H⁺), was prepared in accordancewith the general method of example 32 fromtrans-4-{2-[4-(5,6-difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylaminehydrochloride (example 62, step 1) and acetic acid.

Example 67N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-hydroxy-acetamide

The title compound, MS: m/e=422.2 (M+H⁺), was prepared in accordancewith the general method of example 32 fromtrans-4-{2-[4-(5,6-difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylaminehydrochloride (example 62, step 1) and glycolic acid.

Example 68N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-hydroxy-propionamide

The title compound, MS: m/e=436.0 (M+H⁺), was prepared in accordancewith the general method of example 32 fromtrans-4-{2-[4-(5,6-difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylaminehydrochloride (example 62, step 1) and 3-hydroxypropionic acid.

Example 69N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-hydroxy-cyclohexyl)-acetamide

The title compound, MS: m/e=504.1 (M+H⁺), was prepared in accordancewith the general method of example 40 fromtrans-4-{2-[4-(5,6-difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylaminehydrochloride (example 62, step 1) andtrans-(4-hydroxy-cyclohexyl)-acetic acid potassium salt (prepared frommethyl 4-hydroxyphenyl acetate and Nickel-aluminum alloy in MeOH and byKO^(t)SiMe₃ conversion of the methyl ester to the anhydrous acid saltfollowing Tett. Letters, 25(51), 1984, 5831-5834).

Example 70N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-((1R,3R)-3-hydroxy-cyclopentyl)-acetamide

The title compound, MS: m/e=490.4 (M+H⁺), was prepared in accordancewith the general method of example 40 fromtrans-4-{2-[4-(5,6-difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylaminehydrochloride (example 62, step 1) andrac-trans-(3-hydroxy-cyclopentyl)-acetic acid potassium salt (preparedas described in literature Helvetica Chimica Acta—Vol. 75 (1992) Page1945 and 1950 and by KO^(t)SiMe₃ conversion of the methyl ester to theanhydrous acid salt following Tett. Letters, 25(51), 1984, 5831-5834).

Example 71 Tetrahydro-pyran-4-carboxylic acidtrans-(4-{2-[4-(5,6-difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide

The title compound, MS: m/e=476.3 (M+H⁺), was prepared in accordancewith the general method of example 32 fromtrans-4-{2-[4-(5,6-difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylaminehydrochloride (example 62, step 1) and tetrahydro-pyran-4-carboxylicacid.

Example 72N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-[13]dioxan-2-yl-acetamide

The title compound, MS: m/e=492.3 (M+H⁺), was prepared in accordancewith the general method of example 40 fromtrans-4-{2-[4-(5,6-difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine hydrochloride (example 62,step 1) and 11,31-Dioxan-2-yl-acetic acid potassium salt (prepared asdescribed in example 57, step 1 and by KO^(t)SiMe₃ conversion of themethyl ester to the anhydrous acid salt following Tett. Letters, 25(51),1984, 5831-5834).

Example 73N-trans-(4-{2-[4-(6-Methyl-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamideStep 1:Trans-4-{2-[4-(6-Methyl-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylaminehydrochloride

The title compound, MS: m/e=342.3 (M+H⁺), was prepared in accordancewith the general method of example 58, step 1, 2 and 3 starting from2-fluoro-4-methylbenzaldehyde.

Step 2: N-trans (4-{2-[4-(6Methyl-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide

The title compound, MS: m/e=384.3 (M+H⁺), was prepared in accordancewith the general method of example 32 fromtrans-4-{2-[4-(6-methyl-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylaminehydrochloride and acetic acid.

Example A

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mgMagnesium stearate  1.5 mg  4.5 mg (Kernel Weight) 120.0 mg  350.0 mg Film Coat: Hydroxypropyl methyl cellulose  3.5 mg  7.0 mg Polyethyleneglycol 6000  0.8 mg  1.6 mg Talc  1.3 mg  2.6 mg Iron oxide (yellow) 0.8 mg  1.6 mg Titanium dioxide  0.8 mg  1.6 mg

The active ingredient can be sieved and mixed with microcrystallinecellulose, and the mixture can be granulated with a solution ofpolyvinylpyrrolidone in water. The granulate can be mixed with sodiumstarch glycolate and magnesiumstearate and compressed to yield kernelsof 120 or 350 mg respectively. The kernels then can be lacquered with anaqueous solution/suspension of the above mentioned film coat.

Example B

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0mg  Maize starch 20.0 mg Talc  5.0 mg

The components can be sieved and mixed and filled into capsules of size2.

Example C

Injection solutions can have the following composition:

Compound of formula (I) 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg Sodiumcarbonate to obtain a final pH of 7 Water for injection solutions ad 1.0ml

Example D

Soft gelatin capsules containing the following ingredients can bemanufactured in a conventional manner:

Capsule contents Compound of formula (I) 5.0 mg Yellow wax 8.0 mgHydrogenated Soya bean oil 8.0 mg Partially hydrogenated plant oils 34.0mg Soya bean oil 110.0 mg Weight of capsule contents 165.0 mg Gelatincapsule Gelatin 75.0 mg Glycerol 85% 32.0 mg Karion 83 8.0 mg (drymatter) Titanium dioxide 0.4 mg Iron oxide yellow 1.1 mg

The active ingredient can be dissolved in a warm melting of the otheringredients, and the mixture can be filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules then can be treatedaccording to the usual procedures.

Example E

Sachets containing the following ingredients can be manufactured in aconventional manner:

Compound of formula (I) 50.0 mg Lactose, fine powder 1015.0 mg Microcrystalline cellulose (AVICEL PH 102) 1400.0 mg  Sodiumcarboxymethyl cellulose 14.0 mg Polyvinylpyrrolidone K 30 10.0 mgMagnesium stearate 10.0 mg Flavoring additives  1.0 mg

The active ingredient can be mixed with lactose, microcrystallinecellulose and sodium carboxymethyl cellulose and granulated with amixture of polyvinylpyrrolidone in water. The granulate can be mixedwith magnesium stearate and the flavoring additives and be filled intosachets.

1. A compound of formula (I):

wherein: each X is independently halogen, cyano; C₁₋₆-alkyl, C₁₋₆-alkoxyor C₁₋₆-haloalkyl; n is 0, 1, 2 or 3; R¹ is H or C₁₋₆-alkyl; R² is

R³ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkoxy,C₃₋₁₀-cycloalkyl, aryl, 4 to 10 membered heterocycloalkyl, or 5 to 10membered heteroaryl, each of which is optionally substituted by one tofive substituents selected from the group consisting of: halo, cyano,—SO₂—C₁₋₆-alkyl, hydroxyl, C₁₋₆-alkyl, C₁₋₆-haloalkyl,—OC(O)—C₁₋₆-alkyl, C₁₋₆-alkoxy optionally substituted by one or moreR^(a), C₃₋₁₀-cycloalkyl optionally substituted by one or more R^(a), 4to 10 membered heterocycloalkyl optionally substituted by one or moreR^(a), aryl optionally substituted by one or more R^(a), 5 to 10membered heteroaryl optionally substituted by one or more R^(a), and—NR^(b)R^(c), wherein R^(b) is H or C₁₋₆-alkyl and wherein R^(c) is H,C₁₋₆-alkyl or aryl optionally substituted by one or more R^(a); whereinR^(a) is selected from: halo, cyano, oxo, hydroxyl, halobenzenesulfonyl,C₁₋₆-alkyl C₁₋₆-haloalkyl, —NH(CO)—C₁₋₆-alkyl, di(C₁₋₆)alkylamino,—O(CO)—C₁₋₆-alkyl, C₁₋₆-alkylsulfonyl, C₁₋₆-alkoxy C₁₋₆-haloalkoxy, 4 to10 membered heterocycloalkyl aryl, aryloxy, and 5 to 10 memberedheteroaryl; or a pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1, wherein: each X is independently fluorine orchlorine; n is 0, 1 or 2; R¹ is hydrogen; R² is

and or a pharmaceutically acceptable salt thereof.
 3. The compound ofclaim 1 having formula (Ia):

wherein each X is independently fluorine or chlorine; n is 0, 1 or 2; mis 0, 1, 2 or 3; R⁴ is selected from the group consisting of: halo,cyano, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, di(C₁₋₆)alkylamino,—OC(O)—C₁₋₆-alkyl, C₁₋₆-alkoxy optionally substituted by one or moreR^(a), C₃₋₁₀-cycloalkyl optionally substituted by one or more R^(a), 4to 10 membered heterocycloalkyl optionally substituted by one or moreR^(a), aryl optionally substituted by one or more R^(a), 5 to 10membered heteroaryl optionally substituted by one or more R^(a), and—NR^(b)R^(c), wherein R^(a), R^(b) and R^(c) are as defined in claim 1;or a pharmaceutically acceptable salt thereof.
 4. The compound of claim3, wherein each X is independently fluorine or chlorine; n is 1; m is 0,1 or 2; R⁴ is selected from the group consisting of: halo, C₁₋₆-alkoxyoptionally substituted by one or more R^(a), 6 membered heterocycloalkyloptionally substituted by one or more R^(a), and 5 to 6 memberedheteroaryl optionally substituted by one or more R^(a), wherein R^(a) isselected from halo, oxo, hydroxyl and C₁₋₆-alkyl or a pharmaceuticallyacceptable salt thereof.
 5. The compound of claim 3, selected from thegroup consisting of 3-Fluoro-N-trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide,N-trans (4-{2-[4-(6Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-methoxy-benzamide4-tert-Butoxy-N-trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide,4-Chloro-N-trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide,N-trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-pyrrol-1-yl-benzamide,Benzo[1,3]dioxole-5-carboxylic acid trans(4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,and Benzo[1,3]dioxole-5-carboxylic acid trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide.6. The compound of claim 1 having (Ib):

wherein each X is independently fluorine or chlorine; n is 0, 1 or 2; mand p are each independently 0, 1 or 2; R⁴ and R⁵ are each independentlyselected from the group consisting of: halo, cyano, hydroxy, C₁₋₆-alkyl,C₁₋₆-haloalkyl, —OC(O)—C₁₋₆-alkyl, C₁₋₆-alkoxy optionally substituted byone or more R^(a), C₃₋₁₀-cycloalkyl optionally substituted by one ormore R^(a), 4 to 10 membered heterocycloalkyl optionally substituted byone or more R^(a), aryl optionally substituted by one or more R^(a), 5to 10 membered heteroaryl optionally substituted by one or more R^(a),and —NR^(b)R^(c), Y is oxygen or —SO₂—; one, two or three of A¹, A², A³,A⁴ and A⁵ are nitrogen and the others are CR⁶, or A¹, A², A³, A⁴ and A⁵are CR⁶ wherein each R⁶ is independently hydrogen or R⁷; and each R⁷ isindependently C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyl, amino, C₁₋₆alkylamino,N,N-di-(C₁₋₆alkyl)-amino, halo, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy,hetero-C₁₋₆alkyl, C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfanyl, or cyano; or apharmaceutically acceptable salt thereof.
 7. The compound of claim 6,wherein X is fluorine; n and m are each independently 0 orl; P is 0; R⁴is selected from the group consisting of: halo, cyano, hydroxy,C₁₋₆-alkyl, and C₁₋₆-haloalkyl, Y is oxygen or —SO₂—; one or two of A¹,A², A³, A⁴ and A⁵ are nitrogen and the others are CH₂; or apharmaceutically acceptable salt thereof.
 8. The compound of claim 6,selected from the group consisting of N-trans (4-{2-[4-(6Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide,N-trans(4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide,N-Trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-6-morpholin-4-yl-nicotinamide,5-Morpholin-4-yl-pyrazine-2-carboxylic acid trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,6-Morpholin-4-yl-pyridazine-3-carboxylic acid-trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,2-Morpholin-4-yl-pyrimidine-5-carboxylic acid trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,3-Fluoro-N-trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide,4-(1,1-Dioxo-1,6-thiomorpholin-4-yl)-N-trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide,N-trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-morpholin-4-yl-isonicotinamide,N-trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-piperidin-1-yl-benzamide,N-trans(4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-piperidin-1-yl-benzamide,4-(2,6-Dimethyl-morpholin-4-yl)-N-trans(4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide,4-(2,6-Dimethyl-morpholin-4-yl)-N-trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide,and 4-(1,1-Dioxo-1,6,4-thiomorpholin-4-yl)-N trans (4-{2-[4-(5fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide.9. The compound of claim 1 having formula (Ic):

wherein each X is independently fluorine or chlorine; n is 0, 1 or 2; R⁸and R⁹ form a 3-, 4-, 5-, or 6-membered saturated ring, optionallycomprising one or two heteroatoms selected from oxygen and nitrogen; R¹⁰is selected from the group consisting of halogen, cyano, hydroxy,C₁₋₆-alkyl, C₁₋₆-haloalkyl and C₁₋₆-alkoxy; or a pharmaceuticallyacceptable salt thereof.
 10. The compound of claim 1 having formula(Id):

wherein X₁═H and X₂=fluoro or chloro; or X₂═H and X₁=fluoro or chloro;and R¹¹ is selected from the group consisting of C₁₋₆-alkyl andC₁₋₆-alkoxy, each of which is optionally substituted by halogen,hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy or C₅₋₆-cycloalkylwhich is optionally substituted by C₁₋₆-alkyl or C₁₋₆-alkoxy; or apharmaceutically acceptable salt thereof.
 11. The compound of claim 10having formula (Id′):

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim11, selected from the group consisting of4N-trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide,Tetrahydro-pyran-4-carboxylic acid trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,N-trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,N-trans(4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide,N-trans(4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,Trans4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine,2,3-Dihydro-benzo[1,4]dioxine-2-carboxylic acid trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,N-trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(3-methyl-pyrazol-1-yl)-acetamide,and 3,3,3-Trifluoro-N-trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-propionamide.13. The compound of claim 11, selected from the group consisting of2-(3,5-Dimethoxy-phenyl)-N-trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide,N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide,N-trans (4-{2-[4-(6Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3,3,3-trifluoro-2-hydroxy-propionamide,N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-pyran-2-yl)-acetamide,N-trans (4-{2-[4-(6Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-trans(4-methoxy-cyclohexyl)-acetamide, N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(1,4-dioxa-spiro[4.5]dec-8-yl)-acetamide,and N-trans (4-{2-[4-(6Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3,3-dimethoxy-propionamide.14. The compound of claim 1 having formula (Ie):

wherein X₁═H and X₂=fluoro or chloro; or X₂═H and X₁=fluoro or chloro;and R¹² is selected from the group consisting of halo, hydroxy, cyano,C₁₋₆-alkyl, C₁₋₆-haloalkyl and C₁₋₆-alkoxy; or a pharmaceuticallyacceptable salt thereof.
 15. The compound of claim 14 having formula(Ie′):

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim15, selected from the group consisting of1-Hydroxy-cyclopropanecarboxylic acid trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,and 1-Trifluoromethyl-cyclobutanecarboxylic acid trans(4-{2-[4-(6-fluoro-benzo[α]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide.17. The compound of claim 1 having formula (Ig):

wherein X is fluorine or chlorine; n is 0, 1 or 2; R¹³ is selected fromthe group consisting of C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, aryloptionally substituted by one or more R^(a), and 5 to 10 memberedheteroaryl optionally substituted by one or more R^(a); R^(a) halo,C₁₋₆-alkyl and C₁₋₆-alkoxy; or a pharmaceutically acceptable saltthereof.
 18. The compound of claim 17, selected from the groupconsisting of Ethanesulfonic acid (4-trans{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,4-Chloro-N-trans(4-{2-[4-(6-fluoro-benzo[α]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzenesulfonamide,N-trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-methoxy-benzenesulfonamide,and Pyridine-3-sulfonic acidtrans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide.19. The compound of claim 1, selected from the group consisting of:3-Fluoro-N-trans(4-{2-[4-(6-fluoro-benzo[α]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide,N-trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-methoxy-isonicotinamide,4-(2,6-Dimethyl-morpholin-4-yl)-N-trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide,N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(R)-tetrahydro-pyran-2-yl-acetamide,N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(S)-tetrahydro-pyran-2-yl-acetamide,N-trans (4-{2-[4-(6Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-furan-2-yl)-acetamide,(R)—N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-hydroxy-butyramide,N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-acetamide,N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-((1S,3S)-3-methoxy-cyclopentyl)-acetamide,and N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-4-methyl-cyclohexyl)-acetamide.20. The compound of claim 1, selected from the group consisting ofN-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-trans-methoxy-4-methyl-cyclohexyl)-acetamide,N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-cis-methoxy-4-methyl-cyclohexyl)-acetamide,N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide,(R)—N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide,(S)—N (4-{2-[4-(6Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide,N-trans (4-{2-[4-(6Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-trans(4-methoxymethyl-cyclohexyl)-acetamide, N-trans(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-hydroxy-4-methyl-cyclohexyl)-acetamide,N-trans (4-{2-[4-(6Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-cyano-propionamide,N-trans (4-{2-[4-(6Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-cyano-acetamide,and N-trans (4-{2-[4-(6Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(R)-tetrahydro-furan-2-yl-acetamide.21. The compound of claim 1, selected from the group consisting ofN-trans (4-{2-[4-(6Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-cyclopropyl-acetamide,N-trans (4-{2-[4-(6Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-hydroxy-acetamide,N-trans (4-{2-[4-(6Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-methanesulfonyl-acetamide,N-trans (4-{2-[4-(6Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-[1,3]dioxan-2-yl-acetamide,N-trans (4-{2-[4-(5Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-cyclohexyl)-acetamide,N-trans (4-{2-[4-(5Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-methanesulfonamide,N-trans (4-{2-[4-(6Chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,N-trans (4-{2-[4-(6Chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-furan-2-yl)-acetamide,N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-methoxy-acetamide,andN-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-((1R,3R)-3-methoxy-cyclopentyl)-acetamide.22. The compound of claim 1, selected from the group consisting ofN-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-cyclohexyl)-acetamide,N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide,N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-hydroxy-acetamide,N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-hydroxy-propionamide,N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-hydroxy-cyclohexyl)-acetamide,N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-((1R,3R)-3-hydroxy-cyclopentyl)-acetamide,Tetrahydro-pyran-4-carboxylic acidtrans-(4-{2-[4-(5,6-difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-[1,3]dioxan-2-yl-acetamide,and N-trans (4-{2-[4-(6Methyl-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide.23. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (I):

wherein: each X is independently halogen, cyano; C₁₋₆-alkyl, C₁₋₆-alkoxyor C₁₋₆-haloalkyl; n is 0, 1, 2 or 3; R¹ is H or C₁₋₆-alkyl; R² is

R³ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkoxy,C₃₋₁₀-cycloalkyl, aryl, 4 to 10 membered heterocycloalkyl, or 5 to 10membered heteroaryl, each of which is optionally substituted by one tofive substituents selected from the group consisting of: halo, cyano,—SO₂—C₁₋₆-alkyl, hydroxyl, C₁₋₆-alkyl, C₁₋₆-haloalkyl,—OC(O)—C₁₋₆-alkyl, C₁₋₆-alkoxy optionally substituted by one or moreR^(a), C₃₋₁₀-cycloalkyl optionally substituted by one or more R^(a), 4to 10 membered heterocycloalkyl optionally substituted by one or moreR^(a), aryl optionally substituted by one or more R^(a), 5 to 10membered heteroaryl optionally substituted by one or more R^(a), and—NR^(b)R^(c), wherein R^(b) is H or C₁₋₆-alkyl and wherein R^(a) is H,C₁₋₆-alkyl or aryl optionally substituted by one or more R^(a); whereinR^(a) is selected from: halo, cyano, oxo, hydroxyl, halobenzenesulfonyl,C₁₋₆-alkyl C₁₋₆-haloalkyl, —NH(CO)—C₁₋₆-alkyl, di(C₁₋₆)alkylamino,—O(CO)—C₁₋₆-alkyl, C₁₋₆-alkylsulfonyl, C₁₋₆-alkoxy C₁₋₆-haloalkoxy, 4 to10 membered heterocycloalkyl aryl, aryloxy, and 5 to 10 memberedheteroaryl; or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.